bims-meract 2024-12-01 papers

bims-meract

Biomed News

on Metabolic reprogramming and anti-cancer therapy

Issue of 2024–12–01
25 papers selected by
Andrea Morandi, Università degli Studi di Firenze

Pralatrexate represses the resistance of HCC cells to molecular targeted agents via the miRNA-34a/Notch pathway.
Unraveling lipid metabolism for acute myeloid leukemia therapy.
Cancer Therapies Targeting Cellular Metabolism.
Distinct metabolic phenotype renders β-catenin mutant hepatocellular carcinoma susceptible to treatment-induced ischemia.
Lectin Receptors in Primary and Metastatic Cancer Cells.
Zinc oxide nanoparticles mitigate the malignant progression of ovarian cancer by mediating autophagy-dependent ferroptosis.
The role of metabolic reprogramming in liver cancer and its clinical perspectives.
MAT2a and AHCY inhibition disrupts antioxidant metabolism and reduces glioblastoma cell survival.
STAT2/SLC27A3/PINK1-Mediated Mitophagy Remodeling Lipid Metabolism Contributes to Pazopanib Resistance in Clear Cell Renal Cell Carcinoma.
High expression of malic enzyme 1 predicts adverse prognosis in patients with cytogenetically normal acute myeloid leukaemia and promotes leukaemogenesis through the IL-6/JAK2/STAT3 pathways.
The Role of Adenosine in Overcoming Resistance in Sarcomas.
Unveiling the power of mitochondrial transfer in cancer progression: a perspective in ovarian cancer.
BIRC5 knockdown ameliorates hepatocellular carcinoma progression via regulating PPARγ pathway and cuproptosis.
N-acetylaspartate mitigates pro-inflammatory responses in microglial cells by intersecting lipid metabolism and acetylation processes.
The skeleton: an overlooked regulator of systemic glucose metabolism in cancer?
Urothelial Urinary Bladder Cancer Is Characterized by Stage-Dependent Aberrations in Metabolism of Bioactive Sphingolipids.
Treatment of Melanoma Cells with Chloroquine and Everolimus Activates the Apoptosis Process and Alters Lipid Redistribution.
Selective metabolic regulations by p53 mutant variants in pancreatic cancer.
Aberrant Energy Metabolism in Tumors and Potential Therapeutic Targets.
Aldehyde Dehydrogenase-1A1 (ALDH1A1): The Novel Regulator of Chemoresistance in Pancreatic Cancer Cells.
Sex-dependent effects of CYP2E1 on the kidney and the protective potential of 4MP against cisplatin-induced nephrotoxicity.
Metformin Inhibits the Progression of Pancreatic Cancer Through Regulating miR-378a-3p/VEGFA/RGC-32 Axis.
Research progress of iron metabolism and ferroptosis in myeloid neoplasms.
Mechanical forces inducing oxaliplatin resistance in pancreatic cancer can be targeted by autophagy inhibition.
Emerging role of metabolic reprogramming in the immune microenvironment and immunotherapy of thyroid cancer.

Discov Oncol. 2024 Nov 25. 15(1): 709

Pralatrexate represses the resistance of HCC cells to molecular targeted agents via the miRNA-34a/Notch pathway.

Yang Jin, Qiming Liu, Baisheng Sun, Xiaokang Li, Jiahao Wu, Zhiyuan Lin, Yan Ma, Haijiang Jia.

  Metabolism-related pathways are important targets for intervention in the treatment of hepatocellular carcinoma (HCC), but few studies have reported on the combination of inhibitors of folate metabolism-related enzymes and molecularly targeted drugs for HCC. The results of the present work are the first to reveal the effects of an inhibitor of dihydrofolate reductase (DHFR), pralatrexate, on the sensitivity of HCC cells to molecularly targeted agents examined using multiple assays. In HCC cells, knockdown of DHFR or treatment with pralatrexate enhanced the sensitivity of HCC cells to molecularly targeted agents, such as sorafenib, regorafenib, lenvatinib, cabozantinib, or anlotinib. Mechanically, pralatrexate decreased the methylation rates of miRNA-34a's promoter region to enhance the expression of miRNA-34a. Treatment with pralatrexate inhibited the expression of Notch and its downstream factors by enhancing the expression of miRNA-34a in HCC cells. In clinical specimens, the expression of miRNA-34a was negatively correlated with DHFR expression, while DHFR expression was positively correlated with the Notch intracellular domain (NICD) and downstream factors of the Notch pathway. The expression of miRNA-34a was negatively correlated with DHFR expression, while the methylation rates of miRNA-34a's promoter were positively related to DHFR. The effect of pralatrexate on the metabolic profile of HCC cells is very different from that of small molecule inhibitors related to glycolipid metabolism. Therefore, pralatrexate upregulates the sensitivity of HCC cells to molecularly targeted drugs. These results expand our understanding of folate metabolism and HCC and can help provide more options for HCC treatment.

Keywords:  Dihydrofolate reductase; Drug resistance; Hepatocellular carcinoma; Notch pathway; Promoter methylation; miRNA-34a

DOI:  https://doi.org/10.1007/s12672-024-01572-2
Curr Opin Hematol. 2024 Nov 19.

Unraveling lipid metabolism for acute myeloid leukemia therapy.

Cristiana O'Brien, Courtney L Jones.

PURPOSE OF REVIEW: The aim of this review is to highlight the importance of lipids' intricate and interwoven role in mediating diverse acute myeloid leukemia (AML) processes, as well as potentially novel lipid targeting strategies. This review will focus on new studies of lipid metabolism in human leukemia, particularly highlighting work in leukemic stem cells (LSCs), where lipids were assessed directly as a metabolite.
RECENT FINDINGS: Lipid metabolism is essential to support LSC function and AML survival through diverse mechanisms including supporting energy production, membrane composition, signaling pathways, and ferroptosis. Recent work has highlighted the role of lipid rewiring in metabolic plasticity which can underlie therapy response, the impact of cellular and genetic heterogeneity in AML on lipid metabolism, and the discovery of noncanonical roles of lipid related proteins in AML.
SUMMARY: Recent findings around lipid metabolism clearly demonstrates their importance to our understanding and therapeutic targeting of AML. We have only begun to unravel the regulation and utilization of lipids in this disease. Further, understanding the layered dynamics of lipid homeostasis could provide novel opportunities to target lipid metabolism in AML and LSCs with the potential of improving outcomes for patients with AML.

DOI: https://doi.org/10.1097/MOH.0000000000000853
Cold Spring Harb Perspect Med. 2024 Nov 25. pii: a041657. [Epub ahead of print]

Cancer Therapies Targeting Cellular Metabolism.

Benjamin Morris, Alejandro Gutierrez.

Cancer is caused by mutations that drive aberrant growth, proliferation, and invasion, thus overriding regulatory mechanisms that normally link these processes to organismal needs and cellular physiology. This imposes demands for the production of energy and biomass and for survival in microenvironments that are often nonphysiologic and nutrient-poor, which are met by rewiring of cellular metabolism. The resultant dependence of tumor cells on altered metabolism can induce sensitivity to specific metabolic perturbations that can be exploited for cancer therapy. Some cancers are caused by mutations that impart a novel function to metabolic enzymes, leading to the production of a tumor-promoting metabolite that is dispensable in normal cells, representing an ideal therapeutic target. Tumors can also exploit metabolic regulation of cellular immunity to evade antitumor immune responses, and deciphering this biology has revealed potential targets for therapeutic intervention. Here, we discuss a number of illustrative examples highlighting the therapeutic potential and the challenges of targeting metabolism for cancer therapy.

DOI: https://doi.org/10.1101/cshperspect.a041657
medRxiv. 2024 Nov 19. pii: 2023.09.28.23296283. [Epub ahead of print]

Distinct metabolic phenotype renders β-catenin mutant hepatocellular carcinoma susceptible to treatment-induced ischemia.

Kelley Weinfurtner, Jennifer A Crainic, David Tischfield, Daniel Ackerman, Martin Kurian, Abashai Woodard, Wuyan Li, Isabela Gatmaytan, David Ostrowski, Michael C Soulen, Mandeep Dagli, Susan Shamimi-Noori, Jeffrey Mondschein, Deepak Sudheendra, S William Stavropoulos, Shilpa Reddy, Tamim Khaddash, Emma E Furth, Evan S Siegelman, Stephen J Hunt, Gregory J Nadolski, David Kaplan, Terence P F Gade.

Background & Aims: Transarterial chemoembolization (TACE) is the most common treatment for hepatocellular carcinoma (HCC) worldwide; however, response rates and durability vary widely. With the growing armamentarium of therapies for HCC patients, identifying predictors of response to TACE has become increasingly important for a patient population with limited hepatic reserve. We hypothesized that a distinct metabolic phenotype associated with β-catenin pathway mutations render HCC tumors more susceptible to TACE-induced ischemia.
Material and Methods: HCC patients referred for TACE were enrolled in a prospective cohort study at two academic medical centers from April 2016 to October 2021. Liver biopsies were acquired at the time of TACE, and mutational profiles were determined using next generation sequencing. Tumor response was determined by MRI using modified Response Evaluation Criteria in Solid Tumors. HCC cell lines with and without B-catenin mutations were grown in standard and ischemic cell culture conditions (1% O 2 , low nutrient media). Cell viability was measured by WST-1 reagent and Annexin-V PI assay. ATP concentration and metabolites were measured using CellTiter Glo and a YSI biochemical analyzer, respectively. Mitochondrial function was assessed through Seahorse XF Mito Stress Test.
Results: 53 HCC tumors from 50 HCC patients were biopsied prior to TACE, including 22/53 (41.5%) tumors with β-catenin pathway mutations. Despite larger tumor size (4.9 cm vs 3.0 cm p=0.01), tumors with these mutations demonstrated increased rates of complete response after TACE at first imaging (9/22, 40.9% vs 6/31, 19.4%, p=0.06) and best response (12/22, 54.5% vs 7/31, 22.6%, p=0.02), as well as a longer time to tumor progression (median not yet reached vs 8.3 months, p=0.02). In vitro modeling confirmed that β-catenin mutant HCC cells have reduced viability (21.4% vs 59.9%, p<0.01) and ATP levels (8.47 vs 4.26 pM/cell, p<0.001) under ischemic conditions compared to β-catenin wild type HCC cells. β-catenin mutant HCC cells had a dramatic increase in their susceptibility to glycolysis inhibition that was not seen in wild type HCC cells (0.09 vs 0.79 IC50 ration for ischemic vs standard conditions, p=0.004), suggesting a change from predominantly aerobic to anaerobic metabolism under ischemia specific to β-catenin mutant. This was further supported by increased sensitivity of β-catenin mutant cells to inhibition of the electron transport chain (43.9% vs 59.5%, p=0.02,) as well as significantly higher basal oxygen consumption rates (0.74 vs 0.39 pmoles/min, p=0.04), maximal respiratory capacity (1.46 vs 0.51 pmoles/min, p=0.01) and ATP-linked respiration (0.58 vs 0.29 pmoles/min, p=0.04).
Conclusions: HCC tumors with activating B-catenin pathway mutations demonstrate a superior response to TACE, driven by enhanced susceptibility to ischemia due to a greater dependence on oxidative phosphorylation for bioenergetic homeostasis. These findings hold the potential to provide a molecular basis for treatment selection in patients with HCC.
IMPACT AND IMPLICATIONS: With the growing armamentarium of locoregional and systemic therapies for patients with HCC, identifying predictors of response to individual therapies has become increasingly important for a patient population with limited hepatic reserve. Current treatment guidelines fail to incorporate molecular biomarkers to inform therapy. In a prospective clinical study of HCC patients undergoing transarterial chemoembolization (TACE), we demonstrated that tumors with activating mutations in the Wnt/B-catenin pathway have increased rates of complete response and longer time to local progression. We further characterized this finding in vitro by modeling the post-TACE ischemic environment and demonstrated that B-catenin mutant HCC cells have a distinct metabolic phenotype that renders this subtype more susceptible to ischemia. These findings provide the rationale for genotype-based strategies to enable precision medicine for patients with HCC patients.

DOI: https://doi.org/10.1101/2023.09.28.23296283
Asian Pac J Cancer Prev. 2024 Nov 01. pii: 91402. [Epub ahead of print]25(11): 4027-4034

Lectin Receptors in Primary and Metastatic Cancer Cells.

Yevhen Herasymenko, Kostyantyn Herasymenko, Ruslan Klimanskyi, Oleksandr Herasymenko.

   PURPOSE: The purpose of this study was to detect the distribution of different lectin receptors in primary cancer cells as well as in the case of metastasis, as these biomolecules can potentially predict cancer development in certain tissues and systems.
METHODS: To detect lectin receptors in tumors, the authors used conjugates of lectins purified by affinity chromatography with peroxidase, and studied their localization in paraffin sections of 12 cases of primary cancer and 33 of its metastases.
RESULT: In primary cancers and their metastases, there is a distinct mosaicity in the histotopography of individual lectins, especially peanut and soybean lectin. Mosaicity increases in metastases, which corresponds to the increase in malignancy of tumour cells. Detected cases of metastases with a decrease in mosaicity may be a sign of their monoclonality or a decrease in their malignancy. The study of lectins in the cells of cancer metastases and their comparison with the primary tumour and with each other suggests that in metastases, as a rule, not only signs of malignancy increase, but also the ability of cells to adhere and migrate. Thus, in the process of tumour growth and metastasis, there is a selection of clones of cells that are more prone to the development of new metastases.
CONCLUSIONS: It has been revealed that the growth of a primary immature tumour from the epithelium and its metastases is accompanied by sialylation of the surface of tumour cells, which leads to the fact that tumour cells are not recognized by the system of mononuclear phagocytes and this, naturally, contributes to the progression of tumour growth.

Keywords:  Oncology; affinity chromatography; peroxidase; sialylation; tumour progression

DOI:  https://doi.org/10.31557/APJCP.2024.25.11.4027
J Cancer Res Clin Oncol. 2024 Nov 27. 150(12): 513

Zinc oxide nanoparticles mitigate the malignant progression of ovarian cancer by mediating autophagy-dependent ferroptosis.

Wenli Gu, Caihong Yang.

   BACKGROUND: Previous studies have shown that ZnO-NPs induce autophagy and inhibit the malignant progression of ovarian cancer (OC) cells. This study aims to further explore the mechanism of action of ZnO-NPs on OC.
METHODS: SKOV3 cells were treat with different concentrations of ZnO-NPs and cell proliferation was assessed through EDU staining. A Xenograft tumor model was established and mice were treated with varying doses of ZnO-NPs for 21 days. Tumor volume and the weight of each group of mice were measured, and the expression of KI67 in tumor tissues was analyzed to evaluate tumor proliferation in vivo. The expression of autophagy and ferroptosis-related proteins in cells and tumor tissues was examined through immunofluorescence, ELISA, and western blotting assays. The relationship between ZnO-NPs induced autophagy and ferroptosis was further investigated using the ferroptosis inhibitors Fer-1, autophagy inhibitor 3-MA and siRNA for ATG5 (si-ATG5).
RESULTS: ZnO-NPs dose-dependently reduced the proliferation of SKOV3 cells in vitro. In vivo, both high and low doses of ZnO-NPs effectively inhibited the growth of tumor, reduced pathological damage and the expression of KI67 in tumor tissues. Additionally, ZnO-NPs increased the levels of iron, MDA, 4-HNE, oxidized lipid ROS, ATG5, TFR1, ACSL4, LC3, and Beclin1 in cells and tumor tissues, decreased the expression of SOD, GSH-Px, non-oxidized lipid ROS, GPX4, and p62. Transfection with si-ATG5 or treatment with 3-MA significantly weakened these effects of ZnO-NPs in vitro, with si-ATG5 having a stronger weakening effect on the action of ZnO-NPs than 3-MA. However, ferroptosis inhibitor has a lesser impact on the autophagy of ZnO-NPs-treated SKOV3 cells than the effect of autophagy inhibitors and si-ATG5 on the ferroptosis of ZnO-NPs-treated SKOV3 cells.
CONCLUSION: ZnO-NPs inhibited the malignant progression of SKOV3 cells by inducing autophagy-dependent ferroptosis.

Keywords:  Autophagy-dependent ferroptosis; Malignant progression; Ovarian cancer; SKOV3 cells; ZnO-NPs

DOI:  https://doi.org/10.1007/s00432-024-06029-1
Front Oncol. 2024 ;14 1454161

The role of metabolic reprogramming in liver cancer and its clinical perspectives.

Mengxiao Lu, Yingjie Wu, MinMing Xia, Yixin Zhang.

  Primary liver cancer (PLC), which includes hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA), remains a leading cause of cancer-related death worldwide. Chronic liver diseases, such as hepatitis B and C infections and metabolic dysfunction-associated steatotic liver disease (MASLD), are key risk factors for PLC. Metabolic reprogramming, a defining feature of cancer, enables liver cancer cells to adapt to the demands of rapid proliferation and the challenging tumor microenvironment (TME). This manuscript examines the pivotal role of metabolic reprogramming in PLC, with an emphasis on the alterations in glucose, lipid, and amino acid metabolism that drive tumor progression. The Warburg effect, marked by increased glycolysis, facilitates rapid energy production and biosynthesis of cellular components in HCC. Changes in lipid metabolism, including elevated de novo fatty acid synthesis and lipid oxidation, support membrane formation and energy storage essential for cancer cell survival. Amino acid metabolism, particularly glutamine utilization, supplies critical carbon and nitrogen for nucleotide synthesis and maintains redox homeostasis. These metabolic adaptations not only enhance tumor growth and invasion but also reshape the TME, promoting immune escape. Targeting these metabolic pathways presents promising therapeutic opportunities for PLC. This review underscores the interaction between metabolic reprogramming and tumor immunity, suggesting potential metabolic targets for innovative therapeutic strategies. A comprehensive understanding of PLC's intricate metabolic landscape may lead to more effective treatments and better patient outcomes. Integrating metabolomics, genomics, and proteomics in future research will be vital for identifying precise therapeutic targets and advancing personalized therapies for liver cancer.

Keywords:  Warburg effect; amino acid metabolism; hepatocellular carcinoma; lipid metabolism; liver cancer; metabolic dysfunction-associated steatotic liver disease; metabolic reprogramming

DOI:  https://doi.org/10.3389/fonc.2024.1454161
bioRxiv. 2024 Nov 24. pii: 2024.11.23.624981. [Epub ahead of print]

MAT2a and AHCY inhibition disrupts antioxidant metabolism and reduces glioblastoma cell survival.

Emma C Rowland, Matthew D'Antuono, Anna Jermakowicz, Nagi G Ayad.

Glioblastoma (GBM) is a highly aggressive primary malignant adult brain tumor that inevitably recurs with a fatal prognosis. This is due in part to metabolic reprogramming that allows tumors to evade treatment. We therefore must uncover the pathways mediating these adaptations to develop novel and effective treatments. We searched for genes that are essential in GBM cells as measured by a whole-genome pan-cancer CRISPR screen available from DepMap and identified the methionine metabolism genes MAT2A and AHCY . We conducted genetic knockdown, evaluated mitochondrial respiration, and performed targeted metabolomics to study the function of these genes in GBM. We demonstrate that MAT2A or AHCY knockdown induces oxidative stress, hinders cellular respiration, and reduces the survival of GBM cells. Furthermore, selective MAT2a or AHCY inhibition reduces GBM cell viability, impairs oxidative metabolism, and changes the metabolic profile of these cells towards oxidative stress and cell death. Mechanistically, MAT2a or AHCY regulates spare respiratory capacity, the redox buffer cystathionine, lipid and amino acid metabolism, and prevents DNA damage in GBM cells. Our results point to the methionine metabolic pathway as a novel vulnerability point in GBM.
Significance: We demonstrated that methionine metabolism maintains antioxidant production to facilitate pro-tumorigenic ROS signaling and GBM tumor cell survival. Importantly, targeting this pathway in GBM can potentially reduce tumor growth and improve survival in patients.

DOI: https://doi.org/10.1101/2024.11.23.624981
Research (Wash D C). 2024 ;7 0539

STAT2/SLC27A3/PINK1-Mediated Mitophagy Remodeling Lipid Metabolism Contributes to Pazopanib Resistance in Clear Cell Renal Cell Carcinoma.

Dingheng Lu, Yuxiao Li, Xinyang Niu, Jiazhu Sun, Weitao Zhan, Yuchen Shi, Kai Yu, Suyuelin Huang, Xiaoyan Liu, Liping Xie, Xueyou Ma, Ben Liu.

Background: Clear cell renal cell carcinoma (ccRCC) is a prevalent malignant tumor of the urinary system. While tyrosine kinase inhibitors (TKIs) are currently the first-line treatments for advanced/metastatic ccRCC, patients often develop resistance after TKI therapy. Lipid metabolic reprogramming, a hallmark of tumor progression, contributes to acquired drug resistance in various malignant tumors. Mitophagy, a process that maintains mitochondrial homeostasis, aids tumor cells in adapting to microenvironmental changes and consequently developing drug resistance. Solute carrier family 27 member 3 (SLC27A3), highly expressed in lipid-rich tumors like ccRCC, has been associated with poor prognosis. However, the impact of SLC27A3 and the transcription factor complex containing STAT2 on lipid metabolic reprogramming, mitophagy in ccRCC, and their role in TKI resistance remain unexplored. Methods: 786-O to pazopanib resistance was induced by gradient increase of concentration, and the genes related to lipid metabolism were screened by RNA sequencing. Bioinformatics was used to analyze the differential expression of SLC27A3 and its effect on patient prognosis, and to predict the activated pathway in pazopanib-resistant cells. Lipid droplets (LDs) were detected by Red Oil O and BODIPY probe. Micro-targeted lipidomic of acyl-coenzyme A (CoA) and lipid metabolomics were performed to screen potential metabolites of SLC27A3. The differential expression of SLC27A3 was detected in clinical samples. The differential expression of SLC27A3 and its effect on drug resistance of ccRCC tumor were detected in vitro and in vivo. Mitophagy was detected by electron microscopy, Mtphagy probe, and Western blot. The mitochondrial membrane potential (MMP) and reactive oxygen species (ROS) levels were detected by JC-1 and DCF probes. The binding site of the transcription factor complex to the SLC27A3 promoter was detected by dual-luciferase reporter gene assay. Results: SLC27A3, highly expressed in lipid-rich tumors such as ccRCC and glioblastoma, predicts poor prognosis. SLC27A3 expression level also increased in pazopanib-resistant 786-O cells (786-O-PR) with more LD accumulation compared to parental cells. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis from RNA sequencing showed that PINK1/Parkin-mediated mitophagy pathway was enriched in 786-O-PR. Knockdown of SLC27A3 markedly suppressed LD accumulation and mitophagy, and overcame pazopanib resistance in vitro and in vivo. Moreover, SLC27A3 functions as an acyl-CoA ligase catalyzing the formation of acyl-CoA, which refers to fatty acid oxidation accompanied by ROS production and synthesis of lipid. Overproduced acyl-CoA oxidation in mitochondria resulted in MMP decrease and amounts of ROS production, subsequently triggering PINK1/Parkin-mediated mitophagy. Moreover, mitophagy inhibition led to more ROS accumulation and cell death, indicating that mitophagy can keep ROS at an appropriate level by negative feedback. Mitophagy, simultaneously, prevented fatty acid oxidation in mitochondria by consuming CPT1A, forcing synthesis of triglycerides and cholesterol esters stored in LDs by transforming acyl-CoA, to support ccRCC progression. Besides, we found that STAT2 expression was positively correlated to SLC27A3. Transcriptional factor complex containing STAT2 could bind to the promoter of SLC27A3 mRNA to promote SLC27A3 transcription proved by dual-luciferase reporter assay, which also regulated LD metabolism and activated mitophagy during pazopanib resistance. Conclusion: SLC27A3 is up-regulated in pazopanib-resistant ccRCC and predicts poor prognosis. High expression of SLC27A3 produces excessive metabolites of various long-chain fatty acyl-CoA (12:0-, 16:0-, 17:0-, 20:3-CoA) to enter mitochondria for β-oxidation and produce amounts of ROS activating mitophagy. Subsequent mitophagy/ROS negative feedback controls ROS homeostasis and consumes CPT1A protein within mitochondria to suppress fatty acid β-oxidation, forcing acyl-CoA storage in LDs, mediating pazopanib resistance in ccRCC. Furthermore, STAT2 was identified as a core component of a potential upstream transcriptional factor complex for SLC27A3. Our findings shed new light on the underlying mechanism of SLC27A3 in ccRCC TKI resistance, which may provide a novel therapeutic target for the management of ccRCC.

DOI: https://doi.org/10.34133/research.0539
Ther Adv Hematol. 2024 ;15 20406207241301948

High expression of malic enzyme 1 predicts adverse prognosis in patients with cytogenetically normal acute myeloid leukaemia and promotes leukaemogenesis through the IL-6/JAK2/STAT3 pathways.

Chang Zhang, Wenlu Li, Fei Wu, Zhongwei Lu, Piaorong Zeng, Zeyu Luo, Yixiong Cao, Feng Wen, Junjun Li, Xi Chen, Fujue Wang.

   Background: Progress in improving risk stratification methods for patients with cytogenetically normal acute myeloid leukaemia (CN-AML) remains limited. This study investigates the prognostic significance and potential functional mechanism of malic enzyme 1 (ME1) in CN-AML.
Methods: Gene expression and clinical data of patients with CN-AML were obtained from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets, which were subjected to analysis. The prognostic significance of ME1 was assessed through Kaplan-Meier survival analysis, as well as univariate and multivariate Cox regression analyses. A novel risk model based on ME1 expression levels was developed using TCGA data for predicting CN-AML prognosis. Furthermore, the impact of ME1 silencing on AML cell lines was investigated using the Cell Counting Kit-8 assay and flow cytometry. Gene set enrichment analysis (GSEA) analysis and Western blotting were performed to explore the mechanism of ME1 in CN-AML.
Results: CN-AML patients expressing higher ME1 levels exhibited shorter event-free survival (EFS) and overall survival (OS) compared to those with lower ME1 expression in the TCGA and multiple GEO datasets (all p < 0.05). Univariate and multivariate Cox regression analyses indicated that ME1 expression served as an independent prognostic factor for the EFS (p = 0.024 in TCGA, p = 0.035 in GSE6891) and OS (p = 0.039 in TCGA, p = 0.008 in GSE6891) in patients with CN-AML. The developed risk model demonstrated that patients with CN-AML in the high-risk group had worse survival than those in the low-risk group (hazard ratio: 2.67, 95% confidence interval: 1.54-4.65, p < 0.001) and exhibited strong predictive accuracy for 1-, 3- and 5-year OS (area under the curve = 0.69, 0.75, 0.79, respectively). ME1 knockdown significantly inhibited proliferation and increased apoptosis in AML cells (all p < 0.05). GSEA and Western blotting demonstrated that ME1 regulates the IL-6/JAK2/STAT3 pathway in CN-AML.
Conclusion: Elevated ME1 expression serves as an indicator of poorer prognosis in patients with CN-AML, potentially facilitating leukaemogenesis through the IL-6/JAK2/STAT3 pathway. This suggests that ME1 could be a promising prognostic biomarker and therapeutic target for CN-AML.

Keywords:  IL-6/JAK2/STAT3 pathway; cytogenetically normal acute myeloid leukaemia (CN-AML); malic enzyme 1 (ME1); prognosis

DOI:  https://doi.org/10.1177/20406207241301948
Int J Mol Sci. 2024 Nov 14. pii: 12209. [Epub ahead of print]25(22):

The Role of Adenosine in Overcoming Resistance in Sarcomas.

Marlid Cruz-Ramos, Sara Aileen Cabrera-Nieto, Mario Murguia-Perez, Fernanda Sarahí Fajardo-Espinoza.

  Resistance to systemic therapies in sarcomas poses a significant challenge to improving clinical outcomes. Recent research has concentrated on the tumor microenvironment's role in sarcoma progression and treatment resistance. This microenvironment comprises a variety of cell types and signaling molecules that influence tumor behavior, including proliferation, metastasis, and resistance to therapy. Adenosine, abundant in the tumor microenvironment, has been implicated in promoting immunosuppression and chemoresistance. Targeting adenosine receptors and associated pathways offers a novel approach to enhancing immune responses against tumors, potentially improving immunotherapy outcomes in cancers, including sarcomas. Manipulating adenosine signaling also shows promise in overcoming chemotherapy resistance in these tumors. Clinical trials investigating adenosine receptor antagonists in sarcomas have fueled interest in this pathway for sarcoma treatment. Ultimately, a comprehensive understanding of the tumor and vascular microenvironments, as well as the adenosine pathway, may open new avenues for improving treatment outcomes and overcoming resistance in sarcoma. Further studies and clinical trials are crucial to validate these findings and optimize therapeutic strategies, particularly for osteosarcoma. This study provides a literature review exploring the potential role of the adenosine pathway in sarcomas.

Keywords:  adenosine; chemotherapy resistance; immunotherapy; sarcoma

DOI:  https://doi.org/10.3390/ijms252212209
J Ovarian Res. 2024 Nov 23. 17(1): 233

Unveiling the power of mitochondrial transfer in cancer progression: a perspective in ovarian cancer.

Caixia Wang, Chuan Xie.

  Mitochondria are dynamic organelles integral to metabolic processes, coordination of essential biological pathways, and oncogenesis and tumor progression. Recent studies have revealed that mitochondria can be transferred between cells via multiple mechanisms, implicating their involvement in the pathogenesis and progression of ovarian cancer. This review provides a comprehensive analysis of intercellular mitochondrial transfer within the context of ovarian cancer and its tumor microenvironment. We also propose targeted pathways and therapeutic strategies that could be utilized to modulate diseases associated with mitochondrial transfer therapy. Finally, we examine recent advancements in this field and identify several unresolved questions.

Keywords:  Mitochondrial transfer; Ovarian Cancer; Targeted therapy; Tumor Microenvironment

DOI:  https://doi.org/10.1186/s13048-024-01560-8
Discov Oncol. 2024 Nov 25. 15(1): 706

BIRC5 knockdown ameliorates hepatocellular carcinoma progression via regulating PPARγ pathway and cuproptosis.

Yanxing Mai, Zhuocheng Ji, Yujing Tan, Lei Feng, Jiasheng Qin.

   BACKGROUND: Hepatocellular carcinoma (HCC) with complex molecular carcinogenesis represents a kind of prevalent neoplasm occurring in the liver. The objective of this study is to illustrate the function of baculoviral inhibitor of apoptosis repeat containing 5 (BIRC5) and underlying action mechanisms in HCC progression.
METHODS: Comprehensive bioinformatics methods were conducted to screen differentially expressed genes (DEGs), cuproptosis-associated DEGs, and hub genes. The correlation between BIRC5 and immune cell infiltration, prognosis value was evaluated. The specific effects of BIRC5 silencing on HCC cells was validated by functional assays, and the impact on tumorigenicity and cuproptosis was also elucidated in vivo. Additionally, the effects of BIRC5 deficiency on PPAR pathway were determined using Oroxin A in vitro.
RESULTS: A total of 45 cuproptosis-associated DEGs and 9 hub genes were discovered through bioinformatics. Then 6 core genes were confirmed in Hep-3B and SK-Hep-1 cells with 4 genes upregulated and 2 genes downregulated. Therein, BIRC5 was positively correlated with the infiltration of CD8+ T cells, macrophages, and highly expressed BIRC5 exhibited poor prognosis of overall survival in HCC. Furthermore, BIRC5 deletion inhibited the PPARγ pathway, thereby restraining the malignant phenotypes of HCC cells and tumorigenesis in vivo. Additionally, silencing of BIRC5 contributed to the initiation of cuproptosis in HCC.
CONCLUSIONS: BIRC5 silencing attenuated HCC through blocking PPARγ pathway and regulating cuproptosis, which may offer therapeutic implications against HCC.

Keywords:  BIRC5; Bioinformatics analysis; Cuproptosis; Hepatocellular carcinoma; PPAR pathway

DOI:  https://doi.org/10.1007/s12672-024-01592-y
Cell Commun Signal. 2024 Nov 25. 22(1): 564

N-acetylaspartate mitigates pro-inflammatory responses in microglial cells by intersecting lipid metabolism and acetylation processes.

Federica Felice, Pamela De Falco, Martina Milani, Serena Castelli, Antonella Ragnini-Wilson, Giacomo Lazzarino, Nadia D'Ambrosi, Fabio Ciccarone, Maria Rosa Ciriolo.

   BACKGROUND: Microglia play a crucial role in brain development and repair by facilitating processes such as synaptic pruning and debris clearance. They can be activated in response to various stimuli, leading to either pro-inflammatory or anti-inflammatory responses associated with specific metabolic alterations. The imbalances between microglia activation states contribute to chronic neuroinflammation, a hallmark of neurodegenerative diseases. N-acetylaspartate (NAA) is a brain metabolite predominantly produced by neurons and is crucial for central nervous system health. Alterations in NAA metabolism are observed in disorders such as Multiple Sclerosis and Canavan disease. While NAA's role in oligodendrocytes and astrocytes has been investigated, its impact on microglial function remains less understood.
METHODS: The murine BV2 microglial cell line and primary microglia were used as experimental models. Cells were treated with exogenous NAA and stimulated with LPS/IFN-γ to reproduce the pro-inflammatory phenomenon. HPLC and immunofluorescence analysis were used to study lipid metabolism following NAA treatment. Automated fluorescence microscopy was used to analyze phagocytic activity. The effects on the pro-inflammatory response were evaluated by analysis of protein/mRNA expression and ChIP assay of typical inflammatory markers.
RESULTS: NAA treatment promotes an increase in both lipid synthesis and degradation, and enhances the phagocytic activity of BV2 cells, thus fostering surveillant microglia characteristics. Importantly, NAA decreases the pro-inflammatory state induced by LPS/IFN-γ via the activation of histone deacetylases (HDACs). These findings were validated in primary microglial cells, highlighting the impact on cellular metabolism and inflammatory responses.
CONCLUSIONS: The study highlighted the role of NAA in reinforcing the oxidative metabolism of surveillant microglial cells and, most importantly, in buffering the inflammatory processes characterizing reactive microglia. These results suggest that the decreased levels of NAA observed in neurodegenerative disorders can contribute to chronic neuroinflammation.

Keywords:  Anti-inflammatory response; Histone deacetylases; Lipid turnover; Microglial polarization; NAA; Oxidative metabolism

DOI:  https://doi.org/10.1186/s12964-024-01947-6
Front Oncol. 2024 ;14 1481241

The skeleton: an overlooked regulator of systemic glucose metabolism in cancer?

Rucha Ronghe, Adriana A S Tavares.

  Recent discoveries demonstrated the skeleton's role as an endocrine organ regulating whole-body glucose homeostasis. Glucose metabolism is critical for rapid cell proliferation and tumour growth through increasing glucose uptake and fermentation of glucose to lactate despite being in an aerobic environment. This hypothesis paper discusses emerging evidence on how bones can regulate whole-body glucose homeostasis with potential to impact on tumour growth and proliferation. Moreover, it proposes a clinical link between bone glucose metabolism and prognosis of cancer based on recent clinical trial data. Targeting metabolic pathways related with classic glucose metabolism and also bone metabolism, novel methods of cancer therapy and treatment could be developed. This paper objective is to highlight the need for future research on this altered metabolism with potential to change future management of cancer patients.

Keywords:  bone; cancer; glucose; metabolism; systemic

DOI:  https://doi.org/10.3389/fonc.2024.1481241
Int J Mol Sci. 2024 Nov 05. pii: 11889. [Epub ahead of print]25(22):

Urothelial Urinary Bladder Cancer Is Characterized by Stage-Dependent Aberrations in Metabolism of Bioactive Sphingolipids.

Grzegorz Młynarczyk, Agnieszka Mikłosz, Adrian Chabowski, Marcin Baranowski.

  Although dysregulated sphingolipid metabolism was observed in many malignant tumors, bladder cancer has not yet been examined in this regard. This study aims to investigate the metabolism of bioactive sphingolipids across different stages of urothelial urinary bladder cancer (UBC). Forty-eight patients with UBC were included in this study. The neoplasms were classified as either non-muscle-invasive (NMIBC, n = 24) or muscle-invasive (MIBC, n = 24). Samples of the healthy bladder tissue were taken from the patients who underwent radical cystectomy. The content of sphingolipids was measured using an HPLC method, and the mRNA expression of sphingolipid transporters and metabolizing enzymes was evaluated using RT-PCR. Compared to the healthy bladder tissue, the UBC, regardless of the stage, showed an elevated expression of SphK1, Spns2, and ABCC1. The changes in the level of bioactive sphingolipids were strongly stage-dependent. MIBC showed accumulation of sphingosine-1-phosphate (S1P) and ceramide, whereas the content of these sphingolipids in the NMIBC tumor was not different from that of healthy tissue. Moreover, MIBC, compared to NMIBC, was characterized by higher levels of sphingosine and dihydroceramide. We conclude that profound alterations in sphingolipid metabolism develop upon UBC transition from non-muscle-invasive to muscle-invasive. They include the accumulation of S1P, resulting from the increased availability of sphingosine generated from ceramide, which also builds up due to a further activation of its de novo synthesis. We hypothesize that the dysregulation of S1P metabolism leading to the accumulation of this tumor-promoting sphingolipid contributes to the progression of UBC.

Keywords:  S1PL; TCC; dihydrosphingosine-1-phosphate; sphinganine; sphingosine-1-phosphate lyase; sphingosine-1-phosphate phosphatase; transitional cell carcinoma

DOI:  https://doi.org/10.3390/ijms252211889
Int J Mol Sci. 2024 Nov 15. pii: 12278. [Epub ahead of print]25(22):

Treatment of Melanoma Cells with Chloroquine and Everolimus Activates the Apoptosis Process and Alters Lipid Redistribution.

Dorota Ciołczyk-Wierzbicka, Marta Zarzycka, Wojciech Placha, Grzegorz Zemanek, Karol Wierzbicki.

  The balance between apoptosis and autophagy plays a key role in cancer biology and treatment strategies. The aim of this study was to assess the effect of the mTOR kinase inhibitor everolimus and chloroquine on the regulation of proliferation, caspase-3 activation, and apoptosis in melanoma cells. We studied the activity of caspase-3 and the levels of caspase-3 and -9 using the Western blot technique. Cellular apoptosis was examined using a DNA fragmentation assay, and changes in the cell nucleus and cytoskeleton were examined using fluorescence microscopy DAPI, OA/IP. We also studied the rearrangement of lipid structures using fluorescent dyes: Nile Red and Nile Blue. A low nanomolar concentration of the mTOR kinase inhibitor everolimus in combination with chloroquine activated the apoptosis process and decreased cell proliferation. These changes were accompanied by an obvious change in cell morphology and rearrangement of lipid structures. Alterations in lipid redistribution accompanying the process of apoptosis and autophagy are among the first to occur in the cell and can be easily monitored in in vitro studies. The combination of mTOR inhibitors and chloroquine represents a promising area of research in cancer therapy. It has the potential to enhance treatment efficacy through complementary mechanisms.

Keywords:  apoptosis; chloroquine; everolimus; immunosuppressive treatment; lipids; melanoma

DOI:  https://doi.org/10.3390/ijms252212278
J Exp Clin Cancer Res. 2024 Nov 26. 43(1): 310

Selective metabolic regulations by p53 mutant variants in pancreatic cancer.

Sabrina Caporali, Alessio Butera, Alessia Ruzza, Carlotta Zampieri, Marina Bantula', Sandra Scharsich, Anna-Katerina Ückert, Ivana Celardo, Ian U Kouzel, Luigi Leanza, Andreas Gruber, Joan Montero, Angelo D'Alessandro, Thomas Brunner, Marcel Leist, Ivano Amelio.

   BACKGROUND: Approximately half of all human cancers harbour mutations in the p53 gene, leading to the generation of neomorphic p53 mutant proteins. These mutants can exert gain-of-function (GOF) effects, potentially promoting tumour progression. However, the clinical significance of p53 GOF mutations, as well as the selectivity of individual variants, remains controversial and unclear.
METHODS: To elucidate the metabolic regulations and molecular underpinnings associated with the specific p53R270H and p53R172H mutant variants (the mouse equivalents of human p53R273H and p53R175H, respectively), we employed a comprehensive approach. This included integrating global metabolomic analysis with epigenomic and transcriptomic profiling in mouse pancreatic cancer cells. Additionally, we assessed metabolic parameters such as oxygen consumption rate and conducted analyses of proliferation and cell-cell competition to validate the biological impact of metabolic changes on pancreatic ductal adenocarcinoma (PDAC) phenotype. Our findings were further corroborated through analysis of clinical datasets from human cancer cohorts.
RESULTS: Our investigation revealed that the p53R270H variant, but not p53R172H, sustains mitochondrial function and energy production while also influencing cellular antioxidant capacity. Conversely, p53R172H, while not affecting mitochondrial metabolism, attenuates the activation of pro-tumorigenic metabolic pathways such as the urea cycle. Thus, the two variants selectively control different metabolic pathways in pancreatic cancer cells. Mechanistically, p53R270H induces alterations in the expression of genes associated with oxidative stress and reduction in mitochondrial respiration. In contrast, p53R172H specifically impacts the expression levels of enzymes involved in the urea metabolism. However, our analysis of cell proliferation and cell competition suggested that the expression of either p53R270H or p53R172H does not influence confer any selective advantage to this cellular model in vitro. Furthermore, assessment of mitochondrial priming indicated that the p53R270H-driven mitochondrial effect does not alter cytochrome c release or the apoptotic propensity of pancreatic cancer cells.
CONCLUSIONS: Our study elucidates the mutant-specific impact of p53R270H and p53R172H on metabolism of PDAC cancer cells, highlighting the need to shift from viewing p53 mutant variants as a homogeneous group of entities to a systematic assessment of each specific p53 mutant protein. Moreover, our finding underscores the importance of further exploring the significance of p53 mutant proteins using models that more accurately reflect tumor ecology.

Keywords:  Anti-oxidant capacity; Cancer Metabolism; Gain-of-function; Tumour suppressor

DOI:  https://doi.org/10.1186/s13046-024-03232-3
Genes Chromosomes Cancer. 2024 Nov;63(11): e70008

Aberrant Energy Metabolism in Tumors and Potential Therapeutic Targets.

Shuhao Fan, Jianhua Guo, Hui Nie, Huabao Xiong, Yong Xia.

  Energy metabolic reprogramming is frequently observed during tumor progression as tumor cells necessitate adequate energy production for rapid proliferation. Although current medical research shows promising prospects in studying the characteristics of tumor energy metabolism and developing anti-tumor drugs targeting energy metabolism, there is a lack of systematic compendiums and comprehensive reviews in this field. The objective of this study is to conduct a systematic review on the characteristics of tumor cells' energy metabolism, with a specific focus on comparing abnormalities between tumor and normal cells, as well as summarizing potential targets for tumor therapy. Additionally, this review also elucidates the aberrant mechanisms underlying four major energy metabolic pathways (glucose, lipid, glutamine, and mitochondria-dependent) during carcinogenesis and tumor progression. Through the utilization of graphical representations, we have identified anomalies in crucial energy metabolism pathways, encompassing transporter proteins (glucose transporter, CD36, and ASCT2), signaling molecules (Ras, AMPK, and PTEN), as well as transcription factors (Myc, HIF-1α, CREB-1, and p53). The key molecules responsible for aberrant energy metabolism in tumors may serve as potential targets for cancer therapy. Therefore, this review provides an overview of the distinct energy-generating pathways within tumor cells, laying the groundwork for developing innovative strategies for precise cancer treatment.

Keywords:  energy metabolism abnormality; glucose metabolism; glutamine metabolism; lipid metabolism; oxidative phosphorylation

DOI:  https://doi.org/10.1002/gcc.70008
Cancer Control. 2024 Jan-Dec;31:31 10732748241305835

Aldehyde Dehydrogenase-1A1 (ALDH1A1): The Novel Regulator of Chemoresistance in Pancreatic Cancer Cells.

Hong-Quan Duong, Minh-Cong Hoang, Thi-Hue Nguyen, Phuong-Thoa Nguyen, Van-Thu Le, Thi-Nguyet Dao, Van-Lang Ngo, The-Hung Dang.

  Aldehyde dehydrogenase-1A1 (ALDH1A1), a member of a superfamily of 19 isozymes, exhibits various biological functions and is involved in several important physiological and pathological processes, including those associated with various diseases including cancers such as pancreatic cancer. Chemotherapy is one of the most important strategies for the treatment of pancreatic cancer; however, the chemoresistance exhibited by pancreatic cancer cells is a leading cause of chemotherapy failure. It has been reported that overexpression of ALDH1A1 significantly correlates with poor prognosis and tumor aggressiveness, and is clinically associated with chemoresistance. Additionally, ALDH1A1 may serve as a novel regulator for the diagnosis and prognosis of cancer resistance. In particular, ALDH1A1 can promote cancer progression by facilitating the manifestation of cancer stem cell properties. However, the molecular mechanism by which ALDH1A1 clinically regulates the development of chemoresistance, and its role in prognosis and cancer stem cells, including pancreatic cancer stem cells, remain unclear. Therefore, the current review aims to summarize the clinical functions of ALDH1A1 as a novel regulator of chemoresistance, prognosis, and cancer stem cell development in pancreatic cancer.

Keywords:  aldehyde dehydrogenase-1A1; cancer drug resistance; cancer stem cells; chemoresistance; pancreatic cancer cells

DOI:  https://doi.org/10.1177/10732748241305835
bioRxiv. 2024 Nov 11. pii: 2024.11.10.622845. [Epub ahead of print]

Sex-dependent effects of CYP2E1 on the kidney and the protective potential of 4MP against cisplatin-induced nephrotoxicity.

J Y Akakpo, E Abbott, B L Woolbright, R G Schnellmann, D P Wallace, J A Taylor.

Cisplatin is the most effective chemotherapeutic agent used to treat various solid tumors and is the single most active chemotherapeutic in the management of bladder cancer (BCa). However, the most common adverse effect limiting cisplatin use is nephrotoxicity. Despite extensive mechanistic studies of the pathophysiology of cisplatin-induced nephrotoxicity (CIN), there are currently no clinical antidotes to treat CIN or second-line chemotherapy agents to treat BCa. Previous research demonstrated that CIN develops primarily in the proximal tubules where cisplatin accumulates and induces renal cell death after the formation of a highly reactive cisplatin-thiol metabolite. Recent evidence shows that the drug-metabolizing enzyme CYP2E1 is also involved in CIN, and its inhibition protects against nephrotoxicity. However, whether therapeutic strategies targeted at CYP2E1 may be beneficial in reducing CIN in the clinic has never been explored. Our group previously demonstrated that the clinically available drug, 4-methylpyrazole (4MP), blocks CYP2E1 activity. Thus, the objective of the current study was to examine the protective effect of 4MP in preclinical mouse models and translational human kidney and BCa cell models. C57BL/6J mice were co-treated with an acute (20 mg/kg for 3 days), or chronic (9 mg/kg for 4 weeks) cisplatin regimen, with or without 50 mg/kg 4MP. We show that severe kidney injury induced by cisplatin 3 days after the acute treatment, as indicated by elevated plasma BUN and creatinine, dilated tubules, tubular necrosis, and cast formation in male mice, was absent in female mice, which lack renal CYP2E1 expression. Importantly, cisplatin induced the activity of CYP2E1 in vitro, and inhibition of this activity by 4MP treatment almost completely eliminated CIN in male mice. These findings are relevant to humans because we show that patients do not express CYP2E1 in BCa cells, unlike kidney cells. 4MP also prevented cisplatin-induced cell death in normal human kidney cells without interfering with its anti-cancer effects in human BCa HTB9 cells. In conclusion, our study highlights the critical role of CYP2E1 in mediating sex-specific differences in CIN, and 4MP treatment appears to be a potential prophylactic therapeutic option to prevent CIN in the clinic.

DOI: https://doi.org/10.1101/2024.11.10.622845
Cancer Med. 2024 Dec;13(23): e70446

Metformin Inhibits the Progression of Pancreatic Cancer Through Regulating miR-378a-3p/VEGFA/RGC-32 Axis.

Jinli He, Yixing Luo, Ying Ding, Liang Zhu.

   BACKGROUND: Pancreatic cancer (PC) is a major contributor to global cancer-related mortality. While the inhibitory effect of metformin (Met) on PC has been reported, the underlying mechanism remains elusive.
METHODS: We established BxPC-3 cell models with miR-378a-3p and VEGFA knockdown. The expression of miR-378a-3p, VEGFA, and RGC-32 in PC and normal tissues was analyzed using GEPIA, TCGA databases. Cell proliferation, invasion, migration, and apoptosis were assessed through CCK8, Transwell, wound healing, and flow cytometry.
RESULTS: Significantly lower expression of miR-378a-3p was observed in PC tissues and cells. Knockdown of miR-378a-3p reversed the impact of Met on cell viability in PANC-1 and BxPC3. VEGFA emerged as a potential regulator in PC and a downstream target of miR-378a-3p. The interaction between VEGFA and RGC-32 played a crucial role in PC regulation. Knockdown of VEGFA substantially reversed the impact of miR-378a-3p inhibitor on tumor growth and the epithelial-mesenchymal transition (EMT) process. Moreover, knockdown of VEGFA effectively countered the influence of miR-378a-3p inhibitor on cell viability and the EMT process in BxPC3 cells.
CONCLUSIONS: Met exerted inhibitory effects on PC through the miR-378a-3p/VEGFA/RGC-32 pathway. Strategies targeting the miR-378a-3p/VEGFA/RGC-32 axis represent a novel avenue for the prevention and treatment of PC.

Keywords:  Met; VEGFA; miR‐378a‐3p; pancreatic cancer

DOI:  https://doi.org/10.1002/cam4.70446
Zhejiang Da Xue Xue Bao Yi Xue Ban. 2024 Nov 23. 1-12

Research progress of iron metabolism and ferroptosis in myeloid neoplasms.

Yudi Wang, Weiying Feng, Fudi Wang, Junxia Min.

  Dysregulation of iron metabolism is present in a variety of myeloid neoplasms. The prognosis of acute myeloid leukemia is related to the differential expression of iron metabolism molecules. The prognosis of myelodysplastic syndrome patients with iron overload is poor. Myeloproliferative neoplasms are often characterized by the coexistence of iron deficiency and erythrocytosis, which can be treated by targeting hepcidin. Myeloid tumor cells are susceptible to oxidative damage caused by the accumulation of reactive oxygen species and are sensitive to ferroptosis. Ferroptosis has anti-tumor effect in acute myeloid leukemia and myelodysplastic syndrome. Targeting ferroptosis can reverse imatinib resistance in chronic myeloid leukemia. All above research results indicate that iron metabolism and ferroptosis affect the development and progression of myeloid neoplasms and can be used as their therapeutic targets. This article reviews the characteristics of iron metabolism in the development and progression of myeloid neoplasms, as well as the mechanism of ferroptosis, in order to provide a basis for the development of new therapeutic strategies.

Keywords:  Ferroptosis; Iron metabolism; Mechanism; Myeloid neoplasms; Review

DOI:  https://doi.org/10.3724/zdxbyxb-2024-0211
Commun Biol. 2024 Nov 27. 7(1): 1581

Mechanical forces inducing oxaliplatin resistance in pancreatic cancer can be targeted by autophagy inhibition.

Maria Kalli, Fotios Mpekris, Antonia Charalambous, Christina Michael, Chrystalla Stylianou, Chrysovalantis Voutouri, Andreas G Hadjigeorgiou, Antonia Papoui, John D Martin, Triantafyllos Stylianopoulos.

Pancreatic cancer remains one of the most lethal malignancies, with limited treatment options and poor prognosis. A common characteristic among pancreatic cancer patients is the biomechanically altered tumor microenvironment (TME), which among others is responsible for the elevated mechanical stresses in the tumor interior. Although significant research has elucidated the effect of mechanical stress on cancer cell proliferation and migration, it has not yet been investigated how it could affect cancer cell drug sensitivity. Here, we demonstrated that mechanical stress triggers autophagy activation, correlated with increased resistance to oxaliplatin treatment in pancreatic cancer cells. Our results demonstrate that inhibition of autophagy using hydroxychloroquine (HCQ) enhanced the oxaliplatin-induced apoptotic cell death in pancreatic cancer cells exposed to mechanical stress. The combined treatment of HCQ with losartan, a known modulator of mechanical abnormalities in tumors, synergistically enhanced the therapeutic efficacy of oxaliplatin in murine pancreatic tumor models. Furthermore, our study revealed that the use of HCQ enhanced the efficacy of losartan to alleviate mechanical stress levels and restore blood vessel integrity beyond its role in autophagy modulation. These findings underscore the potential of co-targeting mechanical stresses and autophagy as a promising therapeutic strategy to overcome drug resistance and increase chemotherapy efficacy.

DOI: https://doi.org/10.1038/s42003-024-07268-1
Int Immunopharmacol. 2024 Nov 26. pii: S1567-5769(24)02224-0. [Epub ahead of print]144 113702

Emerging role of metabolic reprogramming in the immune microenvironment and immunotherapy of thyroid cancer.

Shouhua Li, Hengtong Han, Kaili Yang, Xiaoxiao Li, Libin Ma, Ze Yang, Yong-Xun Zhao.

  The metabolic reprogramming of cancer cells is a hallmark of many malignancies. To meet the energy acquisition needs of tumor cells for rapid proliferation, tumor cells reprogram their nutrient metabolism, which is caused by the abnormal expression of transcription factors and signaling molecules related to energy metabolic pathways as well as the upregulation and downregulation of abnormal metabolic enzymes, receptors, and mediators. Thyroid cancer (TC) is the most common endocrine tumor, and immunotherapy has become the mainstream choice for clinical benefit after the failure of surgical, endocrine, and radioiodine therapies. TC change the tumor microenvironment (TME) through nutrient competition and metabolites, causing metabolic reprogramming of immune cells, profoundly changing immune cell function, and promoting immune evasion of tumor cells. A deeper understanding of how metabolic reprogramming alters the TME and controls immune cell fate and function will help improve the effectiveness of TC immunotherapy and patient outcomes. This paper aims to elucidate the metabolic communication that occurs between immune cells around TC and discusses how metabolic reprogramming in TC affects the immune microenvironment and the effectiveness of anti-cancer immunotherapy. Finally, targeting key metabolic checkpoints during metabolic reprogramming, combined with immunotherapy, is a promising strategy.

Keywords:  Immune microenvironment; Immunometabolism; Immunotherapy; Metabolic reprogramming; Thyroid cancers

DOI:  https://doi.org/10.1016/j.intimp.2024.113702