bims-meract 2024-12-08 papers

bims-meract

Biomed News

on Metabolic reprogramming and anti-cancer therapy

Issue of 2024–12–08
25 papers selected by
Andrea Morandi, Università degli Studi di Firenze

Clinical research framework proposal for ketogenic metabolic therapy in glioblastoma.
O-GlcNAcylation in ovarian tumorigenesis and its therapeutic implications.
Regulation of ROS signaling by TIGAR induces cancer-modulating responses in the tumor microenvironment.
Taurine Synthesis by 2-Aminoethanethiol Dioxygenase as a Vulnerable Metabolic Alteration in Pancreatic Cancer.
Stabilization of SQLE mRNA by WTAP/FTO/IGF2BP3-dependent manner in HGSOC: implications for metabolism, stemness, and progression.
Tumor-Associated Microglia Secrete Extracellular ATP to Support Glioblastoma Progression.
Targeting Glycolytic Reprogramming in Cholangiocarcinoma: A Novel Approach for Metabolic Therapy.
Combating PDAC Drug Resistance: The Role of Ref-1 Inhibitors in Accelerating Progress in Pancreatic Cancer Research.
Estrogen regulates PDPK1 to promote cell proliferation in epithelial ovarian cancer.
Energy Stress-induced CircEPB41(2) Promotes Lipogenesis in Hepatocellular Carcinoma.
Repurposing anti-mesothelin CAR-NK immunotherapy against colorectal cancer.
Nrf2 depletion enhanced curcumin therapy effect in gastric cancer by inducing the excessive accumulation of ROS.
Role of ATP citrate lyase and its complementary partner on fatty acid synthesis in gastric cancer.
Pharmacoproteomics reveals energy metabolism pathways as therapeutic targets of ivermectin in ovarian cancer toward 3P medical approaches.
Targeting autophagy in HCC treatment: exploiting the CD147 internalization pathway.
Serine related gene CCT6A promotes metastasis of hepatocellular carcinoma via interacting with RPS3.
Salidroside overcomes cisplatin resistance in ovarian cancer via the inhibition of CRNDE-mediated autophagy.
METTL3-mediated m6A modification regulates the polycomb repressive complex 1 (PRC1) components BMI1 and RNF2 in hepatocellular carcinoma cells.
FAHD1 and mitochondrial metabolism: a decade of pioneering discoveries.
Fra-1 affects chemotherapy sensitivity by inhibiting ferroptosis in gastric cancer cells.
Decreased lncRNA HNF4A-AS1 facilitates resistance to sorafenib-induced ferroptosis of hepatocellular carcinoma by reprogramming lipid metabolism.
The mechanisms of Pin1 as targets for cancer therapy.
Reprogrammed lipid metabolism in advanced resistant cancers: an upcoming therapeutic opportunity.
Photodynamic therapy photosensitizers and photoactivated chemotherapeutics exhibit distinct bioenergetic profiles to impact ATP metabolism.
LMAN2 Promotes Breast Cancer Tumorigenesis and Drug Resistance by Interacting With MAPK9 via Activation of the MAPK Pathway.

BMC Med. 2024 12 05. 22(1): 578

Clinical research framework proposal for ketogenic metabolic therapy in glioblastoma.

Tomás Duraj, Miriam Kalamian, Giulio Zuccoli, Joseph C Maroon, Dominic P D'Agostino, Adrienne C Scheck, Angela Poff, Sebastian F Winter, Jethro Hu, Rainer J Klement, Alicia Hickson, Derek C Lee, Isabella Cooper, Barbara Kofler, Kenneth A Schwartz, Matthew C L Phillips, Colin E Champ, Beth Zupec-Kania, Jocelyn Tan-Shalaby, Fabiano M Serfaty, Egiroh Omene, Gabriel Arismendi-Morillo, Michael Kiebish, Richard Cheng, Ahmed M El-Sakka, Axel Pflueger, Edward H Mathews, Donese Worden, Hanping Shi, Raffaele Ivan Cincione, Jean Pierre Spinosa, Abdul Kadir Slocum, Mehmet Salih Iyikesici, Atsuo Yanagisawa, Geoffrey J Pilkington, Anthony Chaffee, Wafaa Abdel-Hadi, Amr K Elsamman, Pavel Klein, Keisuke Hagihara, Zsófia Clemens, George W Yu, Athanasios E Evangeliou, Janak K Nathan, Kris Smith, David Fortin, Jorg Dietrich, Purna Mukherjee, Thomas N Seyfried.

  Glioblastoma (GBM) is the most aggressive primary brain tumor in adults, with a universally lethal prognosis despite maximal standard therapies. Here, we present a consensus treatment protocol based on the metabolic requirements of GBM cells for the two major fermentable fuels: glucose and glutamine. Glucose is a source of carbon and ATP synthesis for tumor growth through glycolysis, while glutamine provides nitrogen, carbon, and ATP synthesis through glutaminolysis. As no tumor can grow without anabolic substrates or energy, the simultaneous targeting of glycolysis and glutaminolysis is expected to reduce the proliferation of most if not all GBM cells. Ketogenic metabolic therapy (KMT) leverages diet-drug combinations that inhibit glycolysis, glutaminolysis, and growth signaling while shifting energy metabolism to therapeutic ketosis. The glucose-ketone index (GKI) is a standardized biomarker for assessing biological compliance, ideally via real-time monitoring. KMT aims to increase substrate competition and normalize the tumor microenvironment through GKI-adjusted ketogenic diets, calorie restriction, and fasting, while also targeting glycolytic and glutaminolytic flux using specific metabolic inhibitors. Non-fermentable fuels, such as ketone bodies, fatty acids, or lactate, are comparatively less efficient in supporting the long-term bioenergetic and biosynthetic demands of cancer cell proliferation. The proposed strategy may be implemented as a synergistic metabolic priming baseline in GBM as well as other tumors driven by glycolysis and glutaminolysis, regardless of their residual mitochondrial function. Suggested best practices are provided to guide future KMT research in metabolic oncology, offering a shared, evidence-driven framework for observational and interventional studies.

Keywords:  Cancer; Glioblastoma; Glutaminolysis; Metabolism; Precision medicine; Research design; Warburg Effect

DOI:  https://doi.org/10.1186/s12916-024-03775-4
Transl Oncol. 2024 Nov 30. pii: S1936-5233(24)00344-9. [Epub ahead of print]51 102220

O-GlcNAcylation in ovarian tumorigenesis and its therapeutic implications.

Lu Xia, Jie Mei, Min Huang, Dandan Bao, Zhiwei Wang, Yizhe Chen.

  Ovarian cancer is a prevalent malignancy among women, often associated with a poor prognosis. Post-translational modifications (PTMs), particularly O-GlcNAcylation, have been implicated in the progression of ovarian cancer. Emerging evidence indicates that dysregulation of O-GlcNAcylation contributes to the initiation and malignant progression of ovarian cancer. This review discusses the potential role of O-GlcNAcylation in ovarian tumorigenesis, with a focus on its regulation of various cellular signaling pathways, including p53, RhoA/ROCK/MLC, Ezrin/Radixin/Moesin (ERM), and β-catenin. This review also emphasizes the O-GlcNAcylation of critical proteins in ovarian cancer, such as SNAP-23, SNAP-29, E-cadherin, and calreticulin. Additionally, the potential of O-GlcNAcylation to enhance immunotherapy for ovarian cancer patients is explored. Several compounds targeting OGT and OGA in ovarian cancer are also highlighted. Targeting the dynamic and versatile nature of O-GlcNAcylation could undoubtedly contribute to more effective treatments and improved outcomes for ovarian cancer patients.

Keywords:  Immunotherapy; O-GlcNAcylation; OGA; OGT; Ovarian cancer; PTM

DOI:  https://doi.org/10.1016/j.tranon.2024.102220
Proc Natl Acad Sci U S A. 2024 Dec 10. 121(50): e2416076121

Regulation of ROS signaling by TIGAR induces cancer-modulating responses in the tumor microenvironment.

Eric C Cheung, Douglas Strathdee, David Stevenson, Jack Coomes, Karen Blyth, Karen H Vousden.

  The consequences of reactive oxygen species (ROS) in cancer cells are complex and have been shown to both promote and retard tumorigenesis in different models. In mouse models of pancreatic ductal adenocarcinoma (PDAC), loss of the antioxidant defense gene Tigar results in both a reduction in the development of early pancreatic intraepithelial neoplasia and an increase in invasive and metastatic capacity, accompanied by decreased survival of mice lacking pancreatic TIGAR. We previously demonstrated that increased ROS following loss of TIGAR promotes various cancer cell-intrinsic changes that contribute to metastatic capacity, including epithelial to mesenchymal transition, enhanced migration and invasion, and an increase in ERK signaling. In this study, we show that pancreatic overexpression of TIGAR decreases metastatic capacity and migratory phenotypes in an aggressive model of PDAC, consistent with the concept that dynamic modulation of TIGAR in PDAC contributes to the development and progression of these tumors. Using TIGAR deficient and overexpressing mouse models, we find that the impact of modulation of TIGAR and ROS in PDAC cells also has a profound effect on the normal stromal cells surrounding the tumor. Loss of TIGAR promotes the production of cytokines by cancer cells that induce changes in the surrounding fibroblasts to adopt a tumor-supportive phenotype. Furthermore, these cytokines also attract macrophages that support PDAC dissemination and metastasis. Taken together our work shows that TIGAR-modulated ROS in PDAC can control cell intrinsic and extrinsic changes to impact tumor aggression.

Keywords:  oxidative stress; pancreatic cancer; tumor microenvironment

DOI:  https://doi.org/10.1073/pnas.2416076121
Biomol Ther (Seoul). 2024 Dec 05.

Taurine Synthesis by 2-Aminoethanethiol Dioxygenase as a Vulnerable Metabolic Alteration in Pancreatic Cancer.

Hoonsik Nam, Woohyung Lee, Yun Ji Lee, Jin-Mo Kim, Kyung Hee Jung, Soon-Sun Hong, Song Cheol Kim, Sunghyouk Park.

  Pancreatic ductal adenocarcinoma (PDAC) exhibits an altered metabolic profile compared to normal pancreatic tissue. However, studies on actual pancreatic tissues are limited. Untargeted metabolomics analysis was conducted on 54 pairs of tumor and matched normal tissues. Taurine levels were validated via immunohistochemistry (IHC) on separate PDAC and normal tissues. Bioinformatics analysis of transcriptomics and proteomics data evaluated genes associated with taurine metabolism. Identified taurine-associated gene was validated through gene modulation. Clinical implications were evaluated using patient data. Metabolomics analysis showed a 2.51-fold increase in taurine in PDAC compared to normal tissues (n=54). IHC confirmed this in independent samples (n=99 PDAC, 19 normal). Bioinformatics identified 2-aminoethanethiol dioxygenase (ADO) as a key gene modulating taurine metabolism. IHC on a tissue microarray (39 PDAC, 10 normal) confirmed elevated ADO in PDAC. The ADOTaurine axis correlated with PDAC recurrence and disease-free survival. ADO knockdown reduced cancer cell proliferation and tumor growth in a mouse xenograft model. The MEK-related signaling pathway is suggested to be modulated by ADO-Taurine metabolism. Our multi-omics investigation revealed elevated taurine synthesis mediated by ADO upregulation in PDAC. The ADOTaurine axis may serve as a biomarker for PDAC prognosis and a therapeutic target.

Keywords:  ADO; Multi-omics; Pancreatic ductal adenocarcinoma; Prognosis; Taurine

DOI:  https://doi.org/10.4062/biomolther.2024.086
Cell Death Dis. 2024 Dec 01. 15(12): 872

Stabilization of SQLE mRNA by WTAP/FTO/IGF2BP3-dependent manner in HGSOC: implications for metabolism, stemness, and progression.

Rui Hou, Xinrui Sun, Shiyao Cao, Yadong Wang, Luo Jiang.

The metabolic reprogramming in high-grade serous ovarian carcinoma (HGSOC) affects the tumor stemness, which mediates tumor recurrence and progression. Knowledge of the stemness and metabolic characteristics of HGSOC is insufficient. Squalene epoxidase (SQLE), a key enzyme in cholesterol metabolism, was significantly upregulated in HGSOC samples with a fold change of about 4 in the RNA sequencing analysis. SQLE was positively related to peritoneal metastasis and poor prognosis of HGSOC patients. Functionally, SQLE drove cancer cell proliferation and inhibited apoptosis to accelerate HGSOC growth. SQLE was highly expressed in ALDH+CD133+ FACS-sorted cells derived from HGSOC cells and ovarian cancer stem cells (OCSCs)-enriched tumorspheres. SQLE overexpression resulted in enhanced CSC-like properties, including increased tumorsphere formation and stemness markers expression. In vivo, SQLE not only promoted cell line-derived xenografts growth but extended the OCSCs subpopulation of single-cell suspension. Moreover, non-targeted metabolomics profiling from UPLC-MS/MS system identified 90 differential metabolites responding to SQLE overexpression in HGSOC cells. Among them, the dysfunctional metabolisms of cholesterol and glutathione were involved in the maintenance of HGSOC stemness. Previous studies showed the alteration of N6-Methyladenosine (m6A) modification in HGSOC development. Herein, the m6A modification in the 3'UTR and CDS regions of SQLE mRNA was increased due to upregulated methyltransferases WTAP and downregulated demethylases FTO, which was recognized by m6A-binding proteins IGF2BP3, rather than IGF2BP1 or IGF2BP2, thereby stabilizing the SQLE mRNA. These results suggested that SQLE was a novel potential clinical marker for predicting the HGSOC development and prognosis, as well as a potential therapeutic target of HGSOC.

DOI: https://doi.org/10.1038/s41419-024-07257-6
Cancer Res. 2024 Dec 02. 84(23): 4017-4030

Tumor-Associated Microglia Secrete Extracellular ATP to Support Glioblastoma Progression.

Caren Yu-Ju Wu, Yiyun Chen, Ya-Jui Lin, Kuo-Chen Wei, Kwang-Yu Chang, Li-Ying Feng, Ko-Ting Chen, Gordon Li, Alexander Liang Ren, Ryan Takeo Nitta, Janet Yuling Wu, Kwang Bog Cho, Ayush Pant, John Choi, Crystal L Mackall, Lily H Kim, An-Chih Wu, Jian-Ying Chuang, Chiung-Yin Huang, Christopher M Jackson, Pin-Yuan Chen, Michael Lim.

Glioblastoma (GBM) is a highly aggressive brain tumor with poor prognosis and high recurrence rates. The complex immune microenvironment of GBM is highly infiltrated by tumor-associated microglia and macrophages (TAM). TAMs are known to be heterogeneous in their functional and metabolic states and can transmit either protumoral or antitumoral signals to glioma cells. Here, we performed bulk RNA sequencing and single-cell RNA sequencing on samples from patients with GBM, which revealed increased ATP synthase expression and oxidative phosphorylation activity in TAMs located in the tumor core relative to the tumor periphery. Both in vitro and in vivo models displayed similar trends of augmented TAM mitochondrial activity, along with elevated mitochondrial fission, glucose uptake, mitochondrial membrane potential, and extracellular ATP (eATP) production by TAMs in the presence of GBM cells. Tumor-secreted factors, including GM-CSF, induced the increase in TAM eATP production. Elevated eATP in the GBM microenvironment promoted glioma growth and invasion by activating the P2X purinoceptor 7 (P2X7R) on glioma cells. Inhibition of the eATP-P2X7R axis attenuated tumor cell viability in vitro and reduced tumor size and prolonged survival in glioma-bearing mouse models. Overall, this study revealed elevated TAM-derived eATP in GBM and provided the basis for targeting the eATP-P2X7R signaling axis as a therapeutic strategy in GBM. Significance: Glioblastoma-mediated metabolic reprogramming in tumor-associated microglia increases ATP secretion that supports cancer cell proliferation and invasion by activating P2X7R, which can be inhibited to attenuate tumor growth.

DOI: https://doi.org/10.1158/0008-5472.CAN-24-0018
J Inflamm Res. 2024 ;17 9665-9681

Targeting Glycolytic Reprogramming in Cholangiocarcinoma: A Novel Approach for Metabolic Therapy.

Liyuan Hao, Shenghao Li, Qing Peng, Junli Zhang, Jiali Deng, Xiaoyu Hu.

  Cholangiocarcinoma (CCA) is a highly aggressive and poorly prognostic tumor. Due to the lack of early symptoms, diagnosing CCA remains challenging, often occurring at an advanced stage. Therefore, exploring the underlying mechanisms of CCA development and identifying potential biomarkers and therapeutic targets is crucial. Recently, metabolic reprogramming in cancer cells has emerged as a hallmark of the disease. Glycolysis has been identified as a central component of metabolic reprogramming in CCA, with multiple signaling pathways and key enzymes playing significant roles. Additionally, non-coding RNAs (ncRNAs) and post-translational modifications of proteins are also involved in regulating glycolysis in CCA. In this review, we provide a comprehensive summary of the alterations in cancer metabolism and the diverse signaling pathways involved, as they might exert an impact on the development of CCA. Overall, targeting glycolysis holds considerable promise as a crucial strategy for enhancing the therapeutic outcomes of CCA. In addition, we performed a bioinformatic analysis of the relationship between CCA and glycolysis to identify and investigate potential targets. The purpose of this study is to provide a theoretical basis for the development of CCA targets.

Keywords:  HK2; PKM2; cholangiocarcinoma; glycolysis; mechanisms

DOI:  https://doi.org/10.2147/JIR.S497551
J Cell Signal. 2024 ;5(4): 208-216

Combating PDAC Drug Resistance: The Role of Ref-1 Inhibitors in Accelerating Progress in Pancreatic Cancer Research.

Eyram K Kpenu, Mark R Kelley.

  Pancreatic Ductal Adenocarcinoma (PDAC) remains one of the most lethal solid tumor diagnoses given its limited treatment options and dismal prognosis. Its complex tumor microenvironment (TME), heterogeneity, and high propensity for drug resistance are major obstacles in developing effective therapies. Here, we highlight the critical role of Redox effector 1 (Ref-1) in PDAC progression and drug resistance, focusing on its redox regulation of key transcription factors (TFs) such as STAT3, HIF1α, and NF-κB, which are pivotal for tumor survival, proliferation, and immune evasion. We discuss the development of novel Ref-1 inhibitors, including second-generation compounds with enhanced potency and improved pharmacokinetic profiles, which have shown significant promise in preclinical models. These inhibitors disrupt Ref-1's redox function, leading to decreased TF activity and increased chemosensitivity in PDAC cells. We further detail our utilization of advanced preclinical models, such as 3D spheroids, organoids, and Tumor-Microenvironment-on-Chip (T-MOC) systems, which better simulate the complex conditions of the PDAC TME and improve the predictive power of therapeutic responses. By targeting Ref-1 and its associated pathways, in conjunction with improved models, more replicative of PDAC's TME, we are focused on approaches which hold the potential to overcome current therapeutic limitations and advance the development of more effective treatments for PDAC. Our findings suggest that integrating Ref-1 inhibitors into combination therapies could disrupt multiple survival mechanisms within the tumor, offering new hope for improving outcomes in this challenging cancer.

Keywords:  APE1/Ref-1; Drug development; PDAC; PDAC model; Redox inhibition; Redox regulation; Transcription factor

DOI:  https://doi.org/10.33696/signaling.5.126
Heliyon. 2024 Nov 30. 10(22): e40296

Estrogen regulates PDPK1 to promote cell proliferation in epithelial ovarian cancer.

Yajie Wang, Huanchao Chang, Xiuwen Li, Hairong Zhang, Qianqian Zhou, Shengjian Tang, Di Wang.

  Epithelial ovarian cancer (EOC) is a common estrogen-sensitive tumor that poses a serious threat to women 's health, and the mortality rate of EOC ranks first among malignant tumors in females. Studies have indicated a strong link between estrogen abnormality and EOC progression. We accidently found that 3-phosphoinositide-dependent protein kinase-1 (PDPK1) is highly expressed in EOC tissues. Further, estrogen also up-regulates the expression of PDPK1 in EOC cells. Notably, the expression of PDPK1 is controlled strictly, and its expression can determine the fate of cells. However, to date, the molecular mechanism by which estrogen elicits PDPK1 expression in EOC cells, and the role of PDPK1 in estrogen-driven EOC cells are not well defined. In this research, we found that a high expression of PDPK1 was associated with poor prognosis in patients with ovarian cancer. Further, estrogen stimulated the increase of PDPK1 protein expression through estrogen receptor ESR1. The depletion or overexpression of PDPK1 affected the inhibition or amplification of estrogen-driven EOC cell proliferation, and the knockdown of PDPK1 suppressed the migration of EOC cells by estrogen while promoting cell apoptosis. This suggests a critical functional association between estrogen and PDPK1 in the process of EOC. The expression of messenger RNA for cyclin A1, cyclin-dependent kinase 2 (CDK2), matrix metallopeptidase 2 (MMP2), and bcl-2 associated x protein (Bax) is regulated by PDPK1 under estrogen treatment. Our results indicated that PDPK1 plays a role as an oncogene in the development of EOC; hence, elucidating the mechanism by which estrogen promotes EOC progression by regulating PDPK1 expression.

Keywords:  EOC; ESR1; Estrogen; Oncogene; PDPK1

DOI:  https://doi.org/10.1016/j.heliyon.2024.e40296
Cancer Res. 2024 Dec 05.

Energy Stress-induced CircEPB41(2) Promotes Lipogenesis in Hepatocellular Carcinoma.

Yang Yang, Jingjing Luo, Zhongyu Wang, Kaiyue Liu, Keyi Feng, Fang Wang, Yide Mei.

The tumor microenvironment plays a pivotal role in the metabolic reprogramming of cancer cells. A better understanding of the underlying mechanisms regulating cancer metabolism could help identify potential therapeutic targets. Here, we identified circEPB41(2) as a metabolically regulated circular RNA that mediates lipid metabolism in hepatocellular carcinoma (HCC). CircEPB41(2) was induced in response to glucose deprivation via HNRNPA1-dependent alternative splicing. Upregulation of circEPB41(2) led to enhanced lipogenic gene expression that promoted lipogenesis. Mechanistically, circEPB41(2) cooperated with the m6A demethylase FTO to decrease the mRNA stability of the histone deacetylase SIRT6, thereby increasing H3K9ac and H3K27ac levels to activate lipogenic gene expression. Silencing of circEPB41(2) inhibited both in vitro proliferation of HCC cells and in vivo growth of tumor xenografts. Clinically, circEPB41(2) was elevated in HCC, and high circEPB41(2) expression was associated with poor patient prognosis. Overall, this study reveals that circEPB41(2) is an important regulator of lipid metabolic reprogramming and indicates that targeting the circEPB41(2)-FTO-SIRT6 axis could represent a promising anti-cancer strategy for treating HCC.

DOI: https://doi.org/10.1158/0008-5472.CAN-24-1630
J Transl Med. 2024 Dec 04. 22(1): 1100

Repurposing anti-mesothelin CAR-NK immunotherapy against colorectal cancer.

Erica Torchiaro, Marco Cortese, Consalvo Petti, Marco Basirico', Federica Invrea, Alice D'Andrea, Letizia Franco, Dario Sangiolo, Enzo Medico.

BACKGROUND: Colorectal cancer (CRC) is the third most common cancer worldwide, with highly variable prognosis and response to treatment. A large subset of patients does not respond to standard treatments or develops resistance. As an alternative, adoptive immunotherapy based on chimeric antigen receptor (CAR)-transduced immune cells has been proposed, however with significant adverse events. We therefore evaluated alternative CAR targets already tested in other tumour types and employed the natural killer cell line NK-92 for CAR transduction because of its more favourable toxicity profile.
METHODS: As an alternative antigen, we considered mesothelin (MSLN), the most represented target in CAR-based clinical studies for solid tumours. MSLN RNA expression was analysed in large series of CRC tumours (n = 640) and cell lines (n = 150), to evaluate its distribution and to identify MSLN-overexpressing models. NK-92 cells were transduced with anti-MSLN CAR, and subsequently sorted and cloned. Activity of CAR-NK-92 cells against target-expressing ovarian and CRC cells was assessed in vitro and in vivo. Statistical significance of efficacy was evaluated by t-test and log-rank test.
RESULTS: Large-scale expression analysis highlighted that about 10% of CRCs overexpress MSLN at levels comparable to those of ovarian cancer, a typical target of MSLN-CAR-based therapy. Intriguingly, MSLN overexpression is more frequent in poor prognosis and KRAS/BRAF-mutant CRC. Lentiviral transduction of NK-92 cells with the MSLN-CAR, followed by sorting and cloning, led to the identification of one clone, MSLN.CAR.NK-92.cl45, stably expressing the CAR and retaining the NK phenotype. As expected, the clone demonstrated significant in vitro and in vivo activity against ovarian cancer cells. When repurposed against models of CRC expressing high MSLN levels, it displayed comparable efficacy, both in vitro and in vivo. Specificity of the clone was confirmed by the absence of activity on control models with low or absent MSLN.
CONCLUSIONS: Our results provide preclinical evidence that a subset of colorectal cancers expressing high mesothelin levels can be effectively targeted by MSLN-CAR-based immunotherapy. The potential therapeutic impact of these findings is enhanced by the fact that frequently MSLN-overexpressing CRCs display worse prognosis and resistance to standard care.

DOI: https://doi.org/10.1186/s12967-024-05851-y
Sci Rep. 2024 12 04. 14(1): 30165

Nrf2 depletion enhanced curcumin therapy effect in gastric cancer by inducing the excessive accumulation of ROS.

Yan Wang, Shasha Wang, Chenchen Ma, Weiwei Qi, Jing Lv, Mengqi Zhang, Shibo Wang, Rui Wang, Yangyang Lu, Wensheng Qiu.

  Gastric cancer (GC) is the most common malignant tumor of the gastrointestinal tract and currently has a poor clinical outcome. Turmeric's rhizome contains a polyphenolic component called curcumin (Cur), which has been demonstrated to inhibit a variety of tumor cells, such as pancreatic, colon, lung and gastric cancers. However, it remains to be elucidated how Cur functions in GC and what molecular processes underlie it. Here, Cur showed a stronger inhibitory effect on GC cells AGS and HGC27. In addition, Cur's inhibition of GC cells growth was accompanied by increased ROS production, triggering of the Keap1-Nrf2 signaling pathway, and increased transcription of its downstream antioxidant genes HO-1, GCLM, and NQO1. However, when a ROS scavenger NAC was used, the inhibitory effect of Cur on GC cells was reversed. Nuclear factor erythroid 2-related factor 2 (Nrf2) is overexpressed or activated in cancers to shield cancer cells from oxidative damage by responding to oxidative stress (OS). Cur has been found to act as an activator of Nrf2. Notably, compared with Nrf2 knockdown and Cur alone, the combination of the two dramatically increased Cur-induced ROS overaccumulation and inhibition of GC cells proliferation, migration, and invasive abilities. Consistent with in vitro experiments, Cur combined with Nrf2 knockdown significantly inhibited tumor growth in nude mice transplanted with AGS cells. Therefore, we concluded that Nrf2 depletion enhanced Cur therapy effect in GC by inducing the excessive accumulation of ROS, indicating that this is a promising treatment strategy.

Keywords:  Curcumin; Gastric cancer; Oxidative stress; ROS; The Keap1-Nrf2 signaling pathway

DOI:  https://doi.org/10.1038/s41598-024-81375-1
Sci Rep. 2024 12 03. 14(1): 30043

Role of ATP citrate lyase and its complementary partner on fatty acid synthesis in gastric cancer.

Chunlei Li, Wenxuan Liu, Youzhao Liu, Weixing Wang, Wenhong Deng.

  ATP citrate lyase (ACLY) and acyl-CoA short-chain synthetases 2 (ACSS2) are key enzymes in lipid metabolism. We explored the role of ACLY in gastric cancer (GC) and the effect of ACLY and ACSS2 compensation on GC growth. We used immunohistochemistry to verify the expression level of ACLY in GC, shRNA to stably knock down the expression level of ACLY in GC cells. The expression levels of lipid metabolizing enzymes were verified by qPCR and WB, and targeted lipidomics and quantification of lipid metabolism-related indicators helped us to understand the changes in lipid metabolism. Finally, subcutaneous graft tumors validate our findings from in vitro experiments. ACLY is upregulated in GC tissues, downregulation of ACLY reduced lipid accumulation and inhibited GC proliferation, migration, and invasion in vitro. ACSS2 maintains cell growth by compensatory elevation to maintain fatty acid synthesis activity in ACLY-depleted GC cells. Inhibition of ACSS2 enhanced the inhibitory effect of downregulation of ACLY on the growth of transplanted tumors in nude mice. Downregulation of ACLY inhibited GC cell growth in vitro and in vivo. ACSS2 was compensated to increase to maintain cell growth in ACLY-depleted GC cells.

Keywords:  ACLY; ACSS2; Gastric cancer; Lipid metabolism; Treatment

DOI:  https://doi.org/10.1038/s41598-024-81448-1
EPMA J. 2024 Dec;15(4): 711-737

Pharmacoproteomics reveals energy metabolism pathways as therapeutic targets of ivermectin in ovarian cancer toward 3P medical approaches.

Zhijun Li, Na Li, Marie Louise Ndzie Noah, Qianwen Shao, Xianquan Zhan.

   Objective: Ovarian cancer is the malignant tumor with the highest mortality rate in the female reproductive system, enormous socio-economic burden, and limited effective drug therapy. There is an urgent need to find novel effective drugs for ovarian cancer therapy. Our previous in vitro studies demonstrate that ivermectin effectively inhibits ovarian cancer cells and affects energy metabolism pathways. This study aims to clarify in vivo mechanisms and therapeutic targets of ivermectin in the treatment of ovarian cancer to establish predictive biomarkers, guide personalized treatments, and improve preventive strategies in the framework of 3P medicine.
Methods: A TOV-21G tumor-bearing mouse model was constructed based on histopathological data and biochemical parameters. TMT-based proteomic analysis was performed on tumor tissues from the different treatment groups. All significantly differentially abundant proteins were characterized by hierarchical clustering, Gene Ontology (GO) enrichment analyses, and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. In addition, the data were integrated and analyzed with the proteomic data of clinical ovarian cancer tissues from our previous study and the proteomic data of ivermectin intervention in ovarian cancer cells to identify key regulators of ivermectin.
Results: Ivermectin (10 mg/kg) had a significant anti-ovarian cancer effect in mice, with a tumor inhibitory rate of 61.5%. Molecular changes in tumor tissue of ivermectin-treated mice were established, and protein-protein interaction (PPI) analysis showed that the main differential pathway networks included the TCA cycle, propanoate metabolism, 2-0xocarboxyacid metabolism, and other pathways. Integrating our previous clinical ovarian cancer tissue and cell experimental data, this study found that ivermectin significantly interfered with the energy metabolic pathways of ovarian cancer, including glycolysis, TCA cycle, oxidative phosphorylation, and other related pathways.
Conclusions: This study evaluated the anti-ovarian cancer effect in vitro and in vivo, and its specific regulatory effect on energy metabolism. The expressions of drug target molecules in the energy metabolism pathway of ovarian cancer will be used to guide the diagnosis and prevention of ovarian cancer. The significant efficacy of ivermectin will be applied to the treatment of ovarian cancer and personalized medication. This has guiding significance for the clinical diagnosis, treatment, personalized medication, and prognosis evaluation of ovarian cancer.
Supplementary Information: The online version contains supplementary material available at 10.1007/s13167-024-00385-1.

Keywords:  Autophagy; Biomarker guided treatments; Energy metabolism; Ivermectin; Mitochondria; Ovarian cancer; Personalized drug therapy; Pharmacoproteomics; Predictive preventive personalized medicine (PPPM / 3PM); Prognosis evaluation

DOI:  https://doi.org/10.1007/s13167-024-00385-1
Cell Commun Signal. 2024 Dec 03. 22(1): 583

Targeting autophagy in HCC treatment: exploiting the CD147 internalization pathway.

Meirui Qian, Ziyu Wan, Xue Liang, Lin Jing, Huijie Zhang, Heyao Qin, Wenli Duan, Ruo Chen, Tianjiao Zhang, Qian He, Meng Lu, Jianli Jiang.

   BACKGROUND/AIMS: Chemotherapy resistance in liver cancer is a major clinical issue, with CD147 playing a vital role in this process. However, the specific mechanisms underlying these processes remain largely unknown. This study investigates how CD147 internalization leads to cytoprotective autophagy, contributing to chemotherapy resistance in hepatocellular carcinoma (HCC).
METHODS: Utilizing bioinformatics methods for KEGG pathways enrichment and screening key molecules associated with chemotherapy resistance through analyses of GEO and TCGA databases. An overexpression/knockdown system was used to study how CD147 internalization leads to autophagy in vitro and in vivo. The process was observed using microscopes, and molecular interactions and autophagy flux were analyzed. Analyzing the internalization of CD147 intracellular domains and the interaction with G3BP1 in clinical chemotherapy recurrence HCC tissues by immunohistochemistry, tissue immunofluorescence, and mass spectrometry. A tumor xenograft mice model was used to study cytoprotective autophagy induced by CD147 and test the effectiveness of combining cisplatin with an autophagy inhibitor in nude mice models.
RESULTS: In our study, we identified the tumor-associated membrane protein CD147, which implicated in chemoresistance lysosome pathways, by evaluating its protein degree value and betweenness centrality using Cytoscape. Our findings revealed that CD147 undergoes internalization and interacts with G3BP1 following treatment with cisplatin and methyl-β-cyclodextrin, forming a complex that is transported to lysosomes via Rab7A. Notably, higher doses of cisplatin enhanced CD147-mediated lysosomal transport while concurrently inhibiting SG assembly. The CD147-G3BP1 complex additionally inhibits mTOR activity, promoting autophagy and augmenting chemoresistance in hepatoma cells. In vivo studies investigations and analyses of clinical samples revealed that elevated internalization of CD147 is associated with chemotherapy recurrence in liver cancer and the maintenance of stem cells. Mice experiments found that the combined administration of cisplatin and hydroxychloroquine enhanced the efficacy of treatment.
CONCLUSIONS: This study reveals that CD147 internalization and CD147-G3BP1 complex translocation to lysosomes induce cytoprotective autophagy, reducing chemotherapy sensitivity by suppressing mTOR activity. It is also shown that chemotherapy drugs combined with autophagy inhibitors can improve the therapeutic effect of cancer, providing new insights into potential targeted therapeutic approaches in treating HCC.

Keywords:  CD147; Chemoresistance; Cytoprotective autophagy; G3BP1; SG

DOI:  https://doi.org/10.1186/s12964-024-01956-5
Funct Integr Genomics. 2024 Dec 04. 24(6): 225

Serine related gene CCT6A promotes metastasis of hepatocellular carcinoma via interacting with RPS3.

Hongwei Cui, Li Jiang, Yujiao Zhou, You Zhou, Fan Li, Zhenzhen Zhang.

  Metastasis is responsible for approximately 90% of lethality from solid tumors. Metabolic abnormalities are one of the key characteristics of tumor cells, closely associated with tumorigenesis and progression. The de novo synthesis pathway of serine is a key metabolic bypass in glycolysis, which could provide material and energy basis for the rapid proliferation of tumor cells by mediating one-carbon metabolism. The transformation of metabolic patterns is particularly pronounced in HCC, often leading to a high dependence of HCC cells on glycolysis. However, up to now, the underlying relationship between serine metabolism and HCC metastasis remains largely unknown. Through a series of bioinformatics methods, we reported CCT6A, a serine related gene, was particularly associated with metastatic events of HCC. We furtherly demonstrated that CCT6A was highly expressed in HCC cells with high metastatic potential. Gain- and loss-of-function analyses showed that CCT6A could promote HCC cells migration and invasion. Mechanistically, CCT6A was found to be interacted with RPS3, and might potentiate the metastasis of HCC by affecting some metabolic processes. Totally, our results suggest that the metabolic reprogramming induced by interacting between CCT6A and RPS3 could advance HCC metastasis, making the CCT6A/RPS3 axis a promising target for therapeutic intervention.

Keywords:  CCT6A; HCC; Metabolic reprogramming; Metastasis; RPS3; Serine

DOI:  https://doi.org/10.1007/s10142-024-01497-7
Mol Cell Biochem. 2024 Dec 05.

Salidroside overcomes cisplatin resistance in ovarian cancer via the inhibition of CRNDE-mediated autophagy.

Ge Yu, Abiyasi Nanding.

  Cisplatin (DDP) resistance significantly affects the survival rate of patients with ovarian cancer (OC). Autophagy is recognized as a common cause of resistance to DDP. This study aimed to investigate the impact of salidroside on OC progression and explore its potential regulatory effects on DDP resistance and autophagy. A DDP-resistant A2780 (A2780/DDP) cell line was induced by exposure to increasing DDP concentrations. The protein levels of autophagy proteins (p62, Beclin-1, ATG5, and LC3 II/LC3 I), apoptosis proteins (cleaved caspase-3 and cleaved caspase-9), and PI3K/AKT/mTOR pathway were determined by western blotting. Autophagic vacuoles in cells were observed with LC3 dyeing with confocal fluorescent microscopy. Cell viability and apoptosis were evaluated by cell counting kit-8 assays and flow cytometry. RT-qPCR was conducted to measure the relative levels of various lncRNAs in A2780 or A2780/DDP cells. A xenograft model was established by subcutaneous injection of 1 × 107 A2780 cells into the posterior flank of nude mice. Tumor size and weight were recorded. The expression of Ki67, cleaved caspase-3 and LC3 in tumor tissues was assessed by immunohistochemistry staining. The biodistribution of DDP in organs and blood of normal nude mice and tumors of tumor-bearing mice was detected using the ICP-MS. Hematoxylin-eosin staining was used to assess the histopathological changes of kidney, liver, and spleen sections. For in vitro analysis, autophagy was enhanced in DDP-resistant A2780 cells. Additionally, salidroside inhibits DDP resistance to A2780 cells via autophagy inhibition. Mechanistically, salidroside downregulated CRNDE in DDP-resistant A2780 cells. CRNDE knockdown inhibited autophagy, while CRNDE overexpression reversed the protective effects of salidroside. Additionally, salidroside activated the PI3K/AKT/mTOR pathway in DDP-resistant A2780 cells, and inhibition of PI3K reversed the effect of salidroside on inhibiting autophagy and apoptosis of A2780/DDP cells. For in vivo analysis, salidroside inhibited tumor growth, autophagy, and nephrotoxicity of DDP. Additionally, salidroside downregulated CRNDE and activated PI3K/AKT/mTOR signaling in vivo. Salidroside prevents autophagy-mediated DDP resistance in OC by downregulating lncRNA CRNDE and activating the PI3K/AKT/mTOR pathway.

Keywords:  Autophagy; CRNDE; Cisplatin; Ovarian cancer; Resistance; Salidroside

DOI:  https://doi.org/10.1007/s11010-024-05168-w
Mol Cancer Res. 2024 Dec 03.

METTL3-mediated m6A modification regulates the polycomb repressive complex 1 (PRC1) components BMI1 and RNF2 in hepatocellular carcinoma cells.

Tong Wu, Weina Chen, Jinqiang Zhang, Wenbo Ma, Nianli Liu.

Methyltransferase-like 3 (METTL3) is a primary RNA methyltransferase that catalyzes N6-methyladenosine (m6A) modification. The current study aims to further delineate the effect and mechanism of METTL3 in hepatocellular carcinoma (HCC). By using a murine model of hepatocellular cancer development induced via hydrodynamic tail vein injection, we showed that METTL3 enhanced HCC development. In cultured human HCC cell lines (Huh7 and PLC/PRF/5), we observed that stable knockdown of METTL3 by shRNA significantly decreased tumor cell proliferation, colony formation and invasion, in vitro. When Huh7 and PLC/PRF/5 cells with shRNA knockdown of METTL3 were inoculated into the livers of SCID mice, we found that METTL3 knockdown significantly inhibited the growth of HCC xenograft tumors. These findings establish METTL3 as an important oncogene in HCC. Through N6-methyladenosine-sequencing (m6A-Seq), RNA sequencing (RNA-Seq) and subsequent validation studies, we identified BMI1 and RNF2, two key components of the polycomb repressive complex 1 (PRC1), as direct downstream targets of METTL3-mediated m6A modification in HCC cells. Our data indicated that METTL3 catalyzed m6A modification of BMI1 and RNF2 mRNAs which led to increased mRNA stability via the m6A reader proteins IGF2BP1/2/3. Furthermore, we showed that the METTL3 inhibitor, STM2457, significantly inhibited HCC cell growth in vitro and in mice. Collectively, this study provides novel evidence that METTL3 promotes HCC development and progression through m6A modification of BMI1 and RNF2. Our findings suggest that the METTL3-m6A-BMI1/RNF2 signaling axis may represent a new therapeutic target for the treatment of HCC. Implications: The METTL3-m6A-BMI1/RNF2 signaling axis promotes HCC development and progression.

DOI: https://doi.org/10.1158/1541-7786.MCR-24-0362
FEBS J. 2024 Dec 06.

FAHD1 and mitochondrial metabolism: a decade of pioneering discoveries.

Elia Cappuccio, Max Holzknecht, Michèle Petit, Anne Heberle, Yana Rytchenko, Athanasios Seretis, Ciro L Pierri, Hubert Gstach, Pidder Jansen-Dürr, Alexander K H Weiss.

  This review consolidates a decade of research on fumarylacetoacetate hydrolase domain containing protein 1 (FAHD1), a mitochondrial oxaloacetate tautomerase and decarboxylase with profound implications in cellular metabolism. Despite its critical role as a regulator in mitochondrial metabolism, FAHD1 has remained an often-overlooked enzyme in broader discussions of mitochondrial function. After more than 12 years of research, it is increasingly clear that FAHD1's contributions to cellular metabolism, oxidative stress regulation, and disease processes such as cancer and aging warrant recognition in both textbooks and comprehensive reviews. The review delves into the broader implications of FAHD1 in mitochondrial function, emphasizing its roles in mitigating reactive oxygen species (ROS) levels and regulating complex II activity, particularly in cancer cells. This enzyme's significance is further highlighted in the context of aging, where FAHD1's activity has been shown to influence cellular senescence, mitochondrial quality control, and the aging process. Moreover, FAHD1's involvement in glutamine metabolism and its impact on cancer cell proliferation, particularly in aggressive breast cancer subtypes, underscores its potential as a therapeutic target. In addition to providing a comprehensive account of FAHD1's biochemical properties and structural insights, the review integrates emerging hypotheses regarding its role in metabolic reprogramming, immune regulation, and mitochondrial dynamics. By establishing a detailed understanding of FAHD1's physiological roles and therapeutic potential, this work advocates for FAHD1's recognition in foundational texts and resources, marking a pivotal step in its integration into mainstream metabolic research and clinical applications in treating metabolic disorders, cancer, and age-related diseases.

Keywords:  FAHD1; ODx; ROS; TCA cycle; aging and cellular senescence; cancer metabolism; glutamine metabolism; mitochondrial dysfunction; mitochondrial metabolism

DOI:  https://doi.org/10.1111/febs.17345
Cancer Drug Resist. 2024 ;7 44

Fra-1 affects chemotherapy sensitivity by inhibiting ferroptosis in gastric cancer cells.

Feng Zeng, Jiaying Cao, Yan Chen, Jingqiong Tang, Qian He, Shan Liao, Lin Liang, Wentao Li, Siyi Liu, Gengqiu Luo, Yanhong Zhou.

  Aim: Gastric cancer (GC) is one of the common malignant tumors, and most patients with advanced GC often develop chemotherapy resistance, resulting in poor chemotherapy efficacy. Therefore, it is crucial to clarify the specific mechanisms of their chemotherapy resistance. Methods: In this study, we analyzed the correlation between fos-related antigen-1 (Fra-1) and chemotherapy resistance in GC using bioinformatics, cell counting kit-8 (CCK8), and 5-ethynyl-2'-deoxyuridine (EDU) combined with flow cytometry; furthermore, we used energy metabolomics sequencing, combined with ChIP-qPCR technology, to elucidate the specific role of Fra-1 in chemotherapy resistance of GC cells and its related mechanisms. Results: We found that high Fra-1 expression was closely related to chemotherapeutic drugs in GC cells, as demonstrated by bioinformatics analysis combined with EDU and CCK8 experiments. Energy metabolomics combined with in vitro cellular experimental analysis revealed that the pentose phosphate pathway (PPP) was activated in GC cells with high Fra-1 expression, along with an increase in the synthesis of metabolites such as nicotinamide adenine dinucleotide phosphate (NADPH) and glutathione (GSH), a decrease in the level of reactive oxygen species (ROS), and the inhibition of their ferroptosis. In addition, ChIP-qPCR experiments confirmed that Fra-1 binds to the promoter of glucose-6-phosphate dehydrogenase (G6PD), a key rate-limiting enzyme of the PPP, and transcriptionally regulates its expression, which in turn activates the PPP and promotes chemotherapy resistance in GC cells. Conclusion: Our research findings suggest that Fra-1 activates the PPP by upregulating G6PD transcriptional activity and inhibiting its ubiquitination level, inhibiting ferroptosis in GC cells and inducing chemoresistance. This provides an experimental basis for screening potential molecular targets for chemotherapy resistance in GC patients.

Keywords:  Fra-1; G6PD; Gastric cancer; chemotherapy resistance; ferroptosis; pentose phosphate pathway

DOI:  https://doi.org/10.20517/cdr.2024.101
Theranostics. 2024 ;14(18): 7088-7110

Decreased lncRNA HNF4A-AS1 facilitates resistance to sorafenib-induced ferroptosis of hepatocellular carcinoma by reprogramming lipid metabolism.

Yong Zhao, Shengbo Han, Zhu Zeng, Hai Zheng, Yang Li, Fan Wang, Yan Huang, Yingsong Zhao, Wenfeng Zhuo, Guozheng Lv, Hongda Wang, Guangyu Zhao, Eryang Zhao, Yuhang Hu, Ping Hu, Gang Zhao.

  Background: Resistance to sorafenib remains a major challenge in the systemic therapy of liver cancer. However, the involvement of lipid metabolism-related lncRNAs in this process remains unclear. Methods: Different expression levels of lipid metabolism-related lncRNAs in HCC were compared by analysis of Gene Expression Omnibus and The Cancer Genome Atlas databases. The influence of HNF4A-AS1 on sorafenib response was evaluated through analysis of public biobanks, cell cytotoxicity and colony formation assays. The effect of HNF4A-AS1 on sorafenib-induced ferroptosis was measured using lipid peroxidation, glutathione, malondialdehyde, and ROS levels. Furthermore, bioinformatic analyses and lipidomic profiling were conducted to study HNF4A-AS1 involvement in lipid metabolic reprogramming. Mechanistic experiments, including the luciferase reporter assay, RNA pulldown, RNA immunoprecipitation (RIP), methylated RNA immunoprecipitation (MeRIP), and RNA remaining assays, were employed to uncover the downstream targets and regulatory mechanisms of HNF4A-AS1 in sorafenib resistance in HCC. Xenograft and organoid experiments were carried out to assess the impact of HNF4A-AS1 on sorafenib response. Results: Bioinformatics analysis revealed that HNF4A-AS1, a lipid metabolism-related lncRNA, is specifically high-expressed in the normal liver and associated with sorafenib resistance in HCC. We further confirmed that HNF4A-AS1 was downregulated in HCC cells and organoids that resistant to sorafenib. Moreover, both in vitro and in vivo studies demonstrated that HNF4A-AS1 overexpression reversed sorafenib resistance in HCC cells, which was further enhanced by polyunsaturated fatty acids (PUFA) supplementation. Mechanistically, HNF4A-AS1 interacted with METTL3, leading to m6A modification of DECR1 mRNA, which subsequently decreased DECR1 expression via YTHDF3-dependent mRNA degradation. Consequently, decreased HNF4A-AS1 levels caused DECR1 overexpression, leading to decreased intracellular PUFA content and promoting resistance to sorafenib-induced ferroptosis in HCC. Conclusions: Our results indicated the pivotal role of lipid metabolism-related and liver-specific HNF4A-AS1 in inhibiting sorafenib resistance by promoting ferroptosis and suggesting that HNF4A-AS1 might be a potential target for HCC.

Keywords:  HNF4A-AS1; ferroptosis; hepatocellular carcinoma; lipid metabolism; m6A; sorafenib resistance

DOI:  https://doi.org/10.7150/thno.99197
Front Immunol. 2024 ;15 1482088

The mechanisms of Pin1 as targets for cancer therapy.

Chuanfeng Liu, Lingying Dan, Quan Li, Ousman Bajinka, Xingxing Yuan.

  Targeted therapy has considerable promise for the effective eradication of cancer at the primary tumor site prior to subsequent metastasis. Using this therapeutic approach, gaining an understanding of mechanistic cancer models is essential for facilitating the inhibition or suppression of tumor growth. Among different oncogenes and proteins, the protein interacting with never-in-mitosis kinase-1 (Pin1) is particularly important. The interaction between Pin1 and phosphorylated threonine-proline motifs results in significant alterations in protein structure and function. In this review, we provide a comprehensive summary of the processes involving Pin1 and its mechanisms in the context of cancer therapy. Pin1 enhances signaling pathways in a number of different human cancers and plays a pivotal role in the suppressive mechanisms relevant to cancer treatment. It is essential for the regulation of proline-directed phosphorylation and for modulating tumor suppressors. Inhibitors of Pin1, particularly naturally occurring substances, have been found to inhibit the carcinogenic activity of Pin1, and consequently this protein could represent an excellent candidate for novel cancer treatment strategies, offering a valuable therapeutic target in carcinogenesis and treatment resistance.

Keywords:  Pin1 inhibitor; anticancer therapy; cis-trans structure; peptidyl-prolyl isomerase; proline; tumorigenesis

DOI:  https://doi.org/10.3389/fimmu.2024.1482088
Cancer Drug Resist. 2024 ;7 45

Reprogrammed lipid metabolism in advanced resistant cancers: an upcoming therapeutic opportunity.

Mario Cioce, Mariamena Arbitrio, Nicoletta Polerà, Emanuela Altomare, Antonia Rizzuto, Carmela De Marco, Vito Michele Fazio, Giuseppe Viglietto, Maria Lucibello.

  Resistance of cancer to therapy is the main challenge to its therapeutic management and is still an unsolved problem. Rearranged lipid metabolism is a strategy adopted by cancer cells to counteract adversity during their evolution toward aggressiveness and immune evasion. This relies on several mechanisms, ranging from altered metabolic pathways within cancer cells to evolved dynamic crosstalk between cancer cells and the tumor microenvironment (TME), with some cell populations at the forefront of metabolic reprogramming, thereby contributing to the resistance of the whole ecosystem during therapy. Unraveling these mechanisms may contribute to the development of more effective combinatorial therapy in resistant patients. This review highlights the alterations in lipid metabolism that contribute to cancer progression, with a focus on the potential clinical relevance of such findings for the management of therapy resistance.

Keywords:  Metabolic signaling; immune evasion; metastasis; therapy resistance; tumor microenvironment

DOI:  https://doi.org/10.20517/cdr.2024.131
Chem Sci. 2024 Nov 21.

Photodynamic therapy photosensitizers and photoactivated chemotherapeutics exhibit distinct bioenergetic profiles to impact ATP metabolism.

Richard J Mitchell, Dmytro Havrylyuk, Austin C Hachey, David K Heidary, Edith C Glazer.

Energy is essential for all life, and mammalian cells generate and store energy in the form of ATP by mitochondrial (oxidative phosphorylation) and non-mitochondrial (glycolysis) metabolism. These processes can now be evaluated by extracellular flux analysis (EFA), which has proven to be an indispensable tool in cell biology, providing previously inaccessible information regarding the bioenergetic landscape of cell lines, complex tissues, and in vivo models. Recently, EFA demonstrated its utility as a screening tool in drug development, both by providing insights into small molecule-organelle interactions, and by revealing the peripheral and potentially undesired off-target effects small molecules have within cells. Surprisingly, technologies to quantify cellular bioenergetics have not been systematically applied in phototherapy development, leaving open several questions about how the mechanism of action of a compound can impact essential cellular functions. Here, we utilized the Seahorse analyzer to address this question for photosensitizers (PSs) for photodynamic therapy (PDT) and contrast these systems to molecules that photo-release a ligand and thus act as photocages or photoactivated chemotherapeutics (PACT), intending to understand the influence these two classes of compounds have on cellular bioenergetics. EFA results show that acute treatment of A549 lung adenocarcinoma cells with PDT agents induces a quiescent bioenergetic response as a result of mitochondrial respiration shutdown. The loss of oxidative phosphorylation is followed by disruption of glycolysis, which occurs after an initial increase in glycolytic respiration is unable to compensate for the interruption of the electron transport chain (ETC). In contrast, the PACT agents tested had little impact on cellular respiration, and the minor inhibition of these metabolic processes was not related to the mechanism of action, as reflected by a lack of correlation with photoejection efficiency. Notably, a system capable of both generating 1O2 and photo-releasing a ligand exhibited the dominant profile of a PDT agent and induced the quiescent bioenergetic state, indicating potential implications on cellular bioenergetics for so-called dual-action agents. These findings are presented with the aim to provide the necessary groundwork for expanding the application and utility of EFA to phototherapeutics and to highlight the role of metabolic alterations in PDT.

DOI: https://doi.org/10.1039/d4sc05393a
Cancer Med. 2024 Dec;13(23): e70448

LMAN2 Promotes Breast Cancer Tumorigenesis and Drug Resistance by Interacting With MAPK9 via Activation of the MAPK Pathway.

Chen Feng, Pingping Li, Pengtao Liu, Bo Wang, Juan Li, Peijun Liu.

   INTRODUCTION: Breast cancer (BC) is the most prevalent malignancy among women worldwide. Lectin, mannose-binding 2 (LMAN2) is a cargo receptor engaged in the transport and sorting of glycoproteins. Despite its ubiquity, the function and underlying mechanisms of LMAN2 in BC continue to elude understanding.
METHODS: Multiple databases were employed to examine the expression of LMAN2 in breast cancer. Immunohistochemistry(IHC), qRT-PCR, and Western blot were performed to quantify LMAN2 expression in BC cell lines and clinical samples. Heat map analysis and Kaplan-Meier analysis were used to analyze the correlation between LMAN2 and clinicopathological features. SiRNAs and overexpression plasmids were transfected into two BC cells to assess the effect of LMAN2 on malignant phenotypes. Coimmunoprecipitation and immunofluorescence were used to screen for potential interacting proteins. Additionally, tumor subcutaneous xenograft mode was constructed to explore tumor chemoresistance.
RESULT: LMAN2 expression was significantly higher in BC compared to that in matched, adjacent normal tissues, and its higher expression level was correlated with worse patient prognosis. In vitro, we found that LMAN2 functions as an oncogene, promoting BC cell proliferation, cell cycle progression, invasion, and chemoresistance while preventing apoptosis. Coimmunoprecipitation and colocalization experiments confirmed the direct binding of LMAN2 to MAPK9 in BC cells. Our investigation of signaling pathways suggested that LMAN2 is involved in the regulation of the MAPK signaling pathway, utilizing this pathway to confer cisplatin resistance. Furthermore, knockdown of LMAN2 improves the sensitivity of drug-resistant BC cells to cisplatin (DDP) in vivo.
CONCLUSION: LMAN2 was a novel diagnostic and prognostic biomarker for BC that promotes chemoresistance via interaction with MAPK9 and activation of the MAPK pathway.

Keywords:  LMAN2; MAPK pathway; MAPK9; breast cancer; tumorigenesis

DOI:  https://doi.org/10.1002/cam4.70448