bims-meract 2024-12-29 papers

bims-meract

Biomed News

on Metabolic reprogramming and anti-cancer therapy

Issue of 2024–12–29
25 papers selected by
Andrea Morandi, Università degli Studi di Firenze

Lipid droplet formation induced by icaritin derivative IC2 promotes a combination strategy for cancer therapy.
Single-cell multi-omics analysis identifies metabolism-linked epigenetic reprogramming as a driver of therapy-resistant medulloblastoma.
A Collection of Novel Antitumor Agents That Regulate Lipid Metabolism in the Tumor Microenvironment.
Untargeted Metabolomics Reveals Dysregulation of Glycine- and Serine-Coupled Metabolic Pathways in an ALDH1L1-Dependent Manner In Vivo.
Integrative systems-level analysis reveals a contextual crosstalk between hypoxia and global metabolism in human breast tumors.
High-adhesion ovarian cancer cell resistance to ferroptosis: The activation of NRF2/FSP1 pathway by junctional adhesion molecule JAM3.
Inhibiting de novo lipogenesis identifies a therapeutic vulnerability in therapy-resistant colorectal cancer.
Ubiquitin-specific protease 7 maintains c-Myc stability to support pancreatic cancer glycolysis and tumor growth.
Unveiling chemotherapy-induced immune landscape remodeling and metabolic reprogramming in lung adenocarcinoma by scRNA-sequencing.
Metabolic profiling of patient-derived organoids reveals nucleotide synthesis as a metabolic vulnerability in malignant rhabdoid tumors.
Accumulation of microtubule-associated protein tau promotes hepatocellular carcinogenesis through inhibiting autophagosome-lysosome fusion.
Targeting PTGDS Promotes ferroptosis in peripheral T cell lymphoma through regulating HMOX1-mediated iron metabolism.
ASPH dysregulates cell death and induces chemoresistance in hepatocellular carcinoma.
Vodobatinib overcomes cancer multidrug resistance by attenuating the drug efflux function of ABCB1 and ABCG2.
Androgen receptor drives polyamine synthesis creating a vulnerability for prostate cancer.
Metabolic Adaptations To Acute Glucose Uptake Inhibition Converge Upon Mitochondrial Respiration For Leukemia Cell Survival.
Singlet Oxygen-Induced Mitochondrial Reset in Cancer: A Novel Approach for Ovarian Cancer Therapy.
Nonthermal Plasma Boosted Dichloroacetate Induces Metabolic Shifts to Combat Glioblastoma CSCs via Oxidative Stress.
OTULIN confers cisplatin resistance in osteosarcoma by mediating GPX4 protein homeostasis to evade the mitochondrial apoptotic pathway.
Effects of Aging on Glucose and Lipid Metabolism in Mice.
Orchestrated desaturation reprogramming from stearoyl-CoA desaturase to fatty acid desaturase 2 in cancer epithelial-mesenchymal transition and metastasis.
ANGPTL3 overcomes sorafenib resistance via suppression of SNAI1 and CPT1A in liver cancer.
V-ATPase in cancer: mechanistic insights and therapeutic potentials.
Synthetic inhibition of SREBP2 and the mevalonate pathway blocks rhabdomyosarcoma tumor growth in vitro and in vivo and promotes chemosensitization.
Napabucasin-loaded PLGA nanoparticles trigger anti-HCC immune responses by metabolic reprogramming of tumor-associated macrophages.

Chin Med. 2024 Dec 26. 19(1): 178

Lipid droplet formation induced by icaritin derivative IC2 promotes a combination strategy for cancer therapy.

Guosheng Wu, Liang Ying, Qian Zhang, He Xiong, Jie Wang, Sitao Chen, Chen Yang, Yiyuan Jin, Zengwei Lai, Ninghan Feng, Yunjun Ge.

   BACKGROUND: Lipid metabolism is crucial in cancer progression. Lipid droplets (LDs) generated in cancer cells can act as protective mechanisms through alleviating lipotoxicity under stress conditions. We previously developed IC2 from the Chinese medicine icaritin as an inhibitor of stearoyl-CoA desaturase 1 (SCD1). IC2 has been shown to disrupt lipid metabolism and inhibits cancer cell proliferation. However, the impact of IC2 on intracellular LDs and the potential of targeting LD formation for combination cancer therapy remain unexplored.
METHODS: LD formation in cancer cells was analyzed with oil red O or BODIPY staining by microscopy. LD quantification was normalized to the cell number. IC2-induced cellular responses were revealed by transcriptional analysis, real-time PCR, and immunoblotting. Mitochondrial functions were assessed by measuring ATP production and oxygen consumption. The lipid source for LD formation was studied using lipid transporter inhibitors or lipid deprivation. The effect of inhibiting LD formation on IC2's anti-tumor effects was evaluated using MTT assays and apoptosis assays, which was subsequently validated in an in vivo xenografted tumor model.
RESULTS: IC2 exerted anti-tumor effects, resulting in LD formation in various cancer cells. LD formation stimulated by IC2 was independent of extracellular lipid sources and did not result from increased de novo fatty acid (FA) synthesis within the cancer cells. Transcriptional analysis indicated that IC2 disturbed mitochondrial functions, which was confirmed by impaired mitochondrial membrane potential (MMP) and reduced capacity for ATP production and oxygen consumption. Moreover, IC2 treatment led to a greater accumulation of lipids in LDs outside the mitochondria compared with the control group. IC2 inhibited the proliferation of PC3 cells and promoted the apoptosis of the cancer cells. These effects were further enhanced after inhibiting the diacylglycerol acyltransferase 1 (DGAT1), a key intracellular enzyme involved in LD formation. In PC3-xenografted mice, the DGAT1 inhibitor augmented the IC2-induced reduction in tumor growth by modulating LD formation.
CONCLUSION: LD formation is a feedback response to IC2's anti-tumor effects, which compromises the anti-tumor actions. IC2's anti-tumor efficacy can be enhanced by combining it with inhibitors targeting LD formation. This strategy may be extended to other anti-tumor agents that regulate lipid metabolism.

Keywords:  Anti-tumor; DGAT1; Icaritin derivative; Lipid droplet; Mitochondrial function

DOI:  https://doi.org/10.1186/s13020-024-01050-5
Res Sq. 2024 Dec 13. pii: rs.3.rs-5522707. [Epub ahead of print]

Single-cell multi-omics analysis identifies metabolism-linked epigenetic reprogramming as a driver of therapy-resistant medulloblastoma.

Rajeev Vibhakar, Bethany Veo, Dong Wang, John DeSisto, Angela Pierce.

Medulloblastoma (MB) is the most prevalent malignant brain tumor in children, exhibiting clinical and genomic heterogeneity. Of the four major subgroups, Group 3 tumors (MYC-MB), display high levels of MYC and metastasis rates. Despite treatment with surgery, radiation, and chemotherapy, patients with Group 3 MB are more likely to develop aggressive recurrent tumors with poor survival. To examine resistance mechanisms, single nuclei multiome analysis of matched primary and recurrent tumors was performed in this study. A persistent progenitor population supporting resistance to therapy was identified. Additionally, distinct chromatin landscapes are linked to altered transcription and correspond to metabolic reprogramming. In vivo modeling of radiation resistance resolves similar chromatin-based metabolic reprogramming focused on wild-type isocitrate dehydrogenase (IDH1) activity. IDH1 inhibition reverses resistance-mediated chromatin changes and enables radiation re-sensitization. Ultimately, these findings demonstrate the efficacy of single-cell multiome analysis in elucidating resistance mechanisms and identifying novel target pathways for MYC-driven medulloblastoma.

DOI: https://doi.org/10.21203/rs.3.rs-5522707/v1
J Med Chem. 2024 Dec 27.

A Collection of Novel Antitumor Agents That Regulate Lipid Metabolism in the Tumor Microenvironment.

Jiahao Zhang, Sha Xu, Lingfeng Yue, Hongrui Lei, Xin Zhai.

Lipid metabolism disorder is the cause of one of the most significant metabolic changes in tumors. In the process of tumor occurrence and development, tumor cells choose a continuous metabolic adaptation to accommodate the changing environment to the maximum extent possible. In a variety of tumors, the uptake, production, and storage of lipids are generally upregulated. Tumor cells take advantage of lipid metabolism to access basic energy, biofilm components, and signal molecules of the tumor microenvironment required for proliferation, survival, invasion, and metastasis. This Perspective briefly uncovers the main metabolic processes and key factors involved in lipid metabolism reprogramming, mainly related to lipid uptake, de novo synthesis and storage of fatty acids, oxidation of fatty acids, cholesterol synthesis, and related regulatory factors. From a medicinal chemistry perspective, agents against related key targets are reviewed, expecting to pave the way for promising antitumor drugs with prospects for application through lipid metabolism reprogramming.

DOI: https://doi.org/10.1021/acs.jmedchem.4c02809
Metabolites. 2024 Dec 10. pii: 696. [Epub ahead of print]14(12):

Untargeted Metabolomics Reveals Dysregulation of Glycine- and Serine-Coupled Metabolic Pathways in an ALDH1L1-Dependent Manner In Vivo.

Grace Fu, Sabrina Molina, Sergey A Krupenko, Susan Sumner, Blake R Rushing.

  Background: ALDH1L1 plays a crucial role in folate metabolism, regulating the flow of one-carbon groups through the conversion of 10-formyltetrahydrofolate to tetrahydrofolate and CO2 in a NADP+-dependent reaction. The downregulation of ALDH1L1 promotes malignant tumor growth, and silencing of ALDH1L1 is commonly observed in many cancers. In a previous study, Aldh1l1 knockout (KO) mice were found to have an altered liver metabotype, including significant alterations in glycine and serine. Serine and glycine play crucial roles in pathways linked to cancer initiation and progression, including one-carbon metabolism. Objective/Methods: To further investigate the metabolic role of ALDH1L1, an untargeted metabolomic analysis was conducted on the liver and plasma of both KO and wild-type (WT) male and female mice. Since ALDH1L1 affects glycine- and serine-coupled metabolites and metabolic pathways, correlation analyses between liver glycine and serine with other liver or plasma metabolites were performed for both WT and KO mice. Significantly correlated metabolites were input into MetaboAnalyst 5.0 for pathway analysis to uncover metabolic pathways coupled with serine and glycine in the presence or absence of ALDH1L1 expression. Results: This analysis showed substantial alterations in pathways associated with glycine and serine following ALDH1L1 loss, including the amino acid metabolism, antioxidant pathways, fatty acid oxidation, and vitamin B5 metabolism. These results indicate the glycine- and serine-linked metabolic reprogramming following ALDH1L1 loss to support macromolecule biosynthesis and antioxidant defense. Additional research is required to further explore the correlation between specific alterations in these pathways and tumor growth, as well as to identify potential dietary interventions to mitigate the detrimental effects of ALDH1L1 loss.

Keywords:  ALDH1L1; folate; liver; metabolomics; plasma

DOI:  https://doi.org/10.3390/metabo14120696
Mol Oncol. 2024 Dec 27.

Integrative systems-level analysis reveals a contextual crosstalk between hypoxia and global metabolism in human breast tumors.

Raefa Abou Khouzam, Salem Chouaib, Mohammad Askandar Iqbal.

  Hypoxia is known to induce reprogramming of glucose metabolism in cancer. However, the impact of hypoxia on global metabolism remains poorly understood. Here, using the systems approach, we evaluated the potential crosstalk between hypoxia and global metabolism using data from > 2000 breast tumors. Tumor samples were scored for hypoxia and 90 metabolic pathways, and these metrics were subjected to an analysis pipeline. Hypoxia showed a very strong association with metabolic aggression and an overall contextual relationship with metabolism. Out of three (M1, M2, and M3) metabolic types in breast cancer, M3 exhibited the strongest relationship with hypoxia; that is, high hypoxic tumors were also metabolically deregulated. Further, the overall correlation pattern between hypoxia and metabolic pathway scores was specific to each type, with M1 showing maximal sensitivity to hypoxia, followed by M2 and then M3. Experimental validation using metabolic inhibitors on cell lines with high or low hypoxia scores further confirmed the metabolic type-dependence of hypoxia. In addition, evaluation of the impact of hypoxia on cancer pathways other than metabolic ones revealed a potential role of hypoxia in immune evasive characteristic of M3 tumors. Overall, the results suggest a complex interplay between hypoxia and metabolism in the context of human breast tumors, with potential implications for both basic cancer biology and breast cancer therapy.

Keywords:  Warburg effect; breast cancer; cancer metabolism; hypoxia; systems biology

DOI:  https://doi.org/10.1002/1878-0261.13762
Free Radic Biol Med. 2024 Dec 18. pii: S0891-5849(24)01149-3. [Epub ahead of print]228 1-13

High-adhesion ovarian cancer cell resistance to ferroptosis: The activation of NRF2/FSP1 pathway by junctional adhesion molecule JAM3.

Ning Wang, Min Chen, Manting Wu, Yuan Liao, Qing Xia, Zheyou Cai, Chengsi He, Qing Tang, Yuan Zhou, Lei Zhao, Zhengzhi Zou, Yibing Chen, Liping Han.

  Ovarian cancer remains a significant challenge due to the lack of effective treatment and the resistance to conventional therapies. Ferroptosis, a form of regulated cell death characterized by iron-depend and lipid peroxidation, has emerged as a potential therapeutic target in cancer. Ovarian cancer has been reported to exert an "iron addiction" phenotype which makes it is susceptible to ferroptosis inducers. However, we found here that high-adhesion ovarian cancer cells were resistant to ferroptosis. Mechanistically, by PCR array, we identified junctional adhesion molecule 3 (JAM3) as a key mediator of ferroptosis resistance in high-adhesion ovarian cancer cells. Knockdowning and blocking JAM3 sensitized cancer cells to ferroptosis inducers RSL3 and erastin, while JAM3 overexpression conferred resistance to these agents. In addition, JAM3 also promoted ovarian cancer cells resistance to chemotherapeutic agent cisplatin in vitro and in vivo by inhibiting ferroptosis. Furthermore, we demonstrated that JAM3 promoted ferroptosis resistance through NRF2-induced upregulation of FSP1, a critical suppressor of lipid peroxidation. Inhibition of the NRF2/FSP1 pathway eliminated high-adhesion, JAM3 overexpressed ovarian cancer cells resistance to ferroptosis, and decreased cancer cells resistance to cisplatin. Moreover, JAM3 high expression was associated with poor prognosis in patients with ovarian cancer. Altogether, this study provided novel insights into the molecular mechanisms underlying ferroptosis resistance and identify JAM3 as a potential therapeutic target for combating drug resistance in ovarian cancer.

Keywords:  Cell adhesion; FSP1; Ferroptosis; JAM3; Ovarian cancer

DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.12.040
Redox Biol. 2024 Dec 11. pii: S2213-2317(24)00436-1. [Epub ahead of print]79 103458

Inhibiting de novo lipogenesis identifies a therapeutic vulnerability in therapy-resistant colorectal cancer.

Eeshrita Jog, Ashwin Kumar Jainarayanan, Alessandro La Ferlita, Arnab Chakraborty, Afiya Dalwai, Showket Yahya, Anusha Shivashankar, Bhagya Shree Choudhary, Aakash Chandramouli, Mufaddal Kazi, Darshan Jain, Nileema Khapare, Akshaya B, Bushra K Khan, Poonam Gera, Prachi Patil, Rahul Thorat, Nandini Verma, Lalit Sehgal, Avanish Saklani, Siddhesh S Kamat, Sorab N Dalal, Nazia Chaudhary.

  A significant clinical challenge in patients with colorectal cancer (CRC), which adversely impacts patient survival, is the development of therapy resistance leading to a relapse. Therapy resistance and relapse in CRC is associated with the formation of lipid droplets (LD) by stimulating de novo lipogenesis (DNL). However, the molecular mechanisms underlying the increase in DNL and the susceptibility to DNL-targeted therapies remain unclear. Our study demonstrates that colorectal drug-tolerant persister cells (DTPs) over-express Lipin1 (LPIN1), which facilitates the sequestration of free fatty acids into LDs. The increased expression is mediated by the ETS1-PTPN1-c-Src-CEBPβ pathway. Blocking the conversion of free fatty acids into LDs by treatment with statins or inhibiting lipin1 expression disrupts lipid homeostasis, leading to lipotoxicity and ferroptotic cell death in both DTPs and patient-derived organoids (PDOs) in vitro. Ferroptosis inhibitors or N-acetylcysteine (NAC) can alleviate lipid ROS and cell death resulting from lipin1 inhibition. This strategy also significantly reduces tumor growth in CRC DTP mouse xenograft and patient-derived xenograft (PDX) models. Our findings highlight a new metabolic vulnerability in CRC DTPs, PDO, and PDX models and provide a framework for the rational repurposing of statins. Targeting the phosphatidic acid (PA) to diacylglycerol (DAG) conversion to prevent lipid droplet formation could be an effective therapeutic approach for therapy-resistant CRC.

Keywords:  De novo lipogenesis; Drug tolerant persister cells; Ferroptosis; Lipid droplet; Lipin1; Non-responder

DOI:  https://doi.org/10.1016/j.redox.2024.103458
J Transl Med. 2024 Dec 20. 22(1): 1135

Ubiquitin-specific protease 7 maintains c-Myc stability to support pancreatic cancer glycolysis and tumor growth.

Jichun Gu, Xi Xiao, Caifeng Zou, Yishen Mao, Chen Jin, Deliang Fu, Rongkun Li, Hengchao Li.

   BACKGROUND: The typical pathological feature of pancreatic ductal adenocarcinoma (PDAC) is a significant increase in stromal reaction, leading to a hypoxic and poorly vascularized tumor microenvironment. Tumor cells undergo metabolic reprogramming, such as the Warburg effect, yet the underlying mechanisms are not fully understood.
METHODS: Interference and overexpression experiments were conducted to analyze the in vivo and in vitro effects of USP7 on the growth and glycolysis of tumor cells. Small-molecule inhibitors of USP7 and transgenic mouse models of PDAC were employed to assess the consequences of targeting USP7 in PDAC. The molecular mechanism underlying USP7-induced c-Myc stabilization was determined by RNA sequencing, co-IP and western blot analyses.
RESULTS: USP7 is abnormally overexpressed in PDAC and predicts a poor prognosis. Hypoxia and extracellular matrix stiffness can induce USP7 expression in PDAC cells. Genetic silencing of USP7 inhibits the glycolytic phenotypes in PDAC cells, while its overexpression has the opposite effect, as demonstrated by glucose uptake, lactate production, and extracellular acidification rate. Importantly, USP7 promotes PDAC tumor growth in a glycolysis-dependent manner. The small-molecule inhibitor P5091 targeting USP7 effectively suppresses the Warburg effect and cell growth in PDAC. In a transgenic mouse model of PDAC, named KPC, P5091 effectively blocks tumor progression. Mechanistically, USP7 interacts with c-Myc, enhancing its stability and expression, which in turn upregulates expression of glycolysis-related genes.
CONCLUSIONS: This study sheds light on the molecular mechanisms underlying the Warburg effect in PDAC and unveils USP7 as a potential therapeutic target for improving PDAC treatment.

Keywords:  Aerobic glycolysis; Deubiquitinating enzymes; Glucose metabolism; HAUSP

DOI:  https://doi.org/10.1186/s12967-024-05962-6
Elife. 2024 Dec 27. pii: RP95988. [Epub ahead of print]13

Unveiling chemotherapy-induced immune landscape remodeling and metabolic reprogramming in lung adenocarcinoma by scRNA-sequencing.

Yiwei Huang, Gujie Wu, Guoshu Bi, Lin Cheng, Jiaqi Liang, Ming Li, Huan Zhang, Guangyao Shan, Zhengyang Hu, Zhencong Chen, Zongwu Lin, Wei Jiang, Qun Wang, Junjie Xi, Shanye Yin, Cheng Zhan.

  Chemotherapy is widely used to treat lung adenocarcinoma (LUAD) patients comprehensively. Considering the limitations of chemotherapy due to drug resistance and other issues, it is crucial to explore the impact of chemotherapy and immunotherapy on these aspects. In this study, tumor samples from nine LUAD patients, of which four only received surgery and five received neoadjuvant chemotherapy, were subjected to scRNA-seq analysis. In vitro and in vivo assays, including flow cytometry, immunofluorescence, Seahorse assay, and tumor xenograft models, were carried out to validate our findings. A total of 83,622 cells were enrolled for subsequent analyses. The composition of cell types exhibited high heterogeneity across different groups. Functional enrichment analysis revealed that chemotherapy drove significant metabolic reprogramming in tumor cells and macrophages. We identified two subtypes of macrophages: Anti-mac cells (CD45+CD11b+CD86+) and Pro-mac cells (CD45+CD11b+ARG +) and sorted them by flow cytometry. The proportion of Pro-mac cells in LUAD tissues increased significantly after neoadjuvant chemotherapy. Pro-mac cells promote tumor growth and angiogenesis and also suppress tumor immunity. Moreover, by analyzing the remodeling of T and B cells induced by neoadjuvant therapy, we noted that chemotherapy ignited a relatively more robust immune cytotoxic response toward tumor cells. Our study demonstrates that chemotherapy induces metabolic reprogramming within the tumor microenvironment of LUAD, particularly affecting the function and composition of immune cells such as macrophages and T cells. We believe our findings will offer insight into the mechanisms of drug resistance and provide novel therapeutic targets for LUAD in the future.

Keywords:   lung adenocarcinoma; cancer biology; human; metabolic reprogramming; neoadjuvant chemotherapy; phenotype atlas

DOI:  https://doi.org/10.7554/eLife.95988
Cell Rep Med. 2024 Dec 11. pii: S2666-3791(24)00649-9. [Epub ahead of print] 101878

Metabolic profiling of patient-derived organoids reveals nucleotide synthesis as a metabolic vulnerability in malignant rhabdoid tumors.

Marjolein M G Kes, Francisco Morales-Rodriguez, Esther A Zaal, Terezinha de Souza, Natalie Proost, Marieke van de Ven, Marry M van den Heuvel-Eibrink, Jeroen W A Jansen, Celia R Berkers, Jarno Drost.

  Malignant rhabdoid tumor (MRT) is one of the most aggressive childhood cancers for which no effective treatment options are available. Reprogramming of cellular metabolism is an important hallmark of cancer, with various metabolism-based drugs being approved as a cancer treatment. In this study, we use patient-derived tumor organoids (tumoroids) to map the metabolic landscape of several pediatric cancers. Combining gene expression analyses and metabolite profiling using mass spectrometry, we find nucleotide biosynthesis to be a particular vulnerability of MRT. Treatment of MRT tumoroids with de novo nucleotide synthesis inhibitors methotrexate (MTX) and BAY-2402234 lowers nucleotide levels in MRT tumoroids and induces apoptosis. Lastly, we demonstrate in vivo efficacy of MTX in MRT patient-derived xenograft (PDX) mouse models. Our study reveals nucleotide biosynthesis as an MRT-specific metabolic vulnerability, which can ultimately lead to better treatment options for children suffering from this lethal pediatric malignancy.

Keywords:  DHODH inhibitor; Methotrexate; cancer metabolism; isotope tracing; malignant rhabdoid tumors; metabolomics; nucleotide synthesis; pediatric kidney cancer

DOI:  https://doi.org/10.1016/j.xcrm.2024.101878
Mol Cell Biochem. 2024 Dec 24.

Accumulation of microtubule-associated protein tau promotes hepatocellular carcinogenesis through inhibiting autophagosome-lysosome fusion.

Xuemin Liu, Zhiwei Hao, Huanhuan He, Xuan Wang, Wenqi Wang, Xiji Shu, Binlian Sun, Zhiyong Hu, Shaobo Hu, Xiaoying Hou, Yue Xiao, Hongyan Zhou, Yuchen Liu, Jianzhi Wang, Zhengqi Fu.

  Dysregulated expression of microtubule-associated protein tau (MAPT) has been reported in a variety of human cancers. However, whether and how Tau influences hepatocellular carcinogenesis remains elusive. This study was aimed to investigate the role and the underlying mechanism of Tau in the proliferation, invasion, migration and sorafenib sensitivity of hepatocellular carcinoma (HCC) cells. An increased level of Tau was found in the primary tumor samples of HCC compared with the adjacent normal liver tissues, and the increase of Tau was positively correlated with p62 evidenced by the data obtained from The Cancer Genome Atlas (TCGA), Gene Expression Profiling Interactive Analysis (GEPIA), and human samples from HCC patients. The high Tau expression was also correlated with a poorer survival in HCC patients demonstrated by using the GEPIA survival analysis and OncoLnc database. Further studies showed that Tau overexpression promoted the growth, invasion and migration and decreased sorafenib sensitivity in HepG2 and Huh7 cells; Tau also accelerated growth of xenograft tumors with blockage of autophagosome-lysosome fusion. Finally, overexpressing Tau inhibited AMPK, which contributed to Tau-induced promotion of hepatocellular carcinogenesis. In conclusion, our study provides the proof-of-concept evidence validating Tau as an attractive HCC target.

Keywords:  Autophagy; Hepatocellular carcinoma; Microtubule-associated protein tau; p62

DOI:  https://doi.org/10.1007/s11010-024-05193-9
Br J Cancer. 2024 Dec 20.

Targeting PTGDS Promotes ferroptosis in peripheral T cell lymphoma through regulating HMOX1-mediated iron metabolism.

Shunfeng Hu, Bingyu Liu, Juanjuan Shang, Qianqian Guo, Tiange Lu, Xiaoli Zhou, Xiangxiang Zhou, Xin Wang.

BACKGROUND: Peripheral T cell lymphoma (PTCL) is characterized by high heterogeneity, strong aggressiveness, and extremely poor prognosis. Ferroptosis, a novel form of programmed cell death, has been involved in tumor development and targeting ferroptosis holds great potential for tumor therapy.
METHODS: Lentiviral transfection was performed to regulate gene expression, followed by Tandem mass tag (TMT)-mass spectrometry and RNA-sequencing. Tumor xenograft models were established for in vivo experiments.
RESULTS: High expression of prostaglandin D2 synthase (PTGDS) was closely associated with poor prognosis of PTCL patients. PTGDS knockdown and AT56 treatment significantly inhibited the progression of PTCL through regulating cell viability, proliferation, apoptosis, cell cycle and invasion in vitro and in vivo. We further revealed that targeting PTGDS promoted ferroptosis process and enhanced the sensitivity of PTCL cells to ferroptosis inducers Sorafenib in vitro and in vivo. Mechanically, PTGDS interacted with heme-degrading enzymes HMOX1, and targeting PTGDS increased the level of iron and induced ferroptosis in PTCL through promoting HMOX1-mediated heme catabolism and ferritin autophagy process. Through the construction of H25A mutation, the specific gene site of HMOX1 corresponding to its role was identified.
CONCLUSIONS: Taken together, our findings firstly identified that targeting PTGDS promotes the ferroptosis in PTCL through regulating HMOX1-mediated iron metabolism, and highlighted novel therapeutic strategies to improve the efficacy of ferroptosis-targeted therapy in PTCL patients.

DOI: https://doi.org/10.1038/s41416-024-02919-w
Cancer Lett. 2024 Dec 18. pii: S0304-3835(24)00791-2. [Epub ahead of print] 217396

ASPH dysregulates cell death and induces chemoresistance in hepatocellular carcinoma.

Jingtao Li, Guocai Zhong, Fengli Hu, Yingnan Zhang, Xiaohang Ren, Zongwen Wang, Shuoheng Ma, Qiankun Zhu, Junwei Li, Shicong Zeng, Yao Zhang, Ting Wang, Qiushi Lin, Xiaoqun Dong, Bo Zhai.

  Hepatocellular carcinoma (HCC) is resistant to multiple conventional drugs including sorafenib, leading to poor prognosis. Inducing cell death has been inextricably pursued in therapeutics, although targeted therapy and immunotherapy have made very limited progress. ASPH (Aspartate β-hydroxylase) can be breakthrough in meeting this unmet clinical need. In HCC, high expression of ASPH enhanced proliferation, migration and invasion. High levels of ASPH predicted worse clinical outcomes of sorafenib-treated HCC patients. Mechanistically, ASPH upregulated SQSTM1/P62 and SLC7A11-GPX4 axis, thereby promoting tumor cell autophagy but blocking ferroptosis. Sorafenib-induced enhancement of autophagy was attenuated by knockout (KO) of ASPH, resulting in sensitization of tumor cells to sorafenib. By silencing ASPH combined with sorafenib, senescence, apoptosis and ferroptosis were mediated, whereas proliferation, migration, invasion, tube formation and stemness were inhibited. As validated by in vivo murine models of HCC, ASPH promoted tumor growth, distant metastasis, and resistance to sorafenib. By contrast, KO ASPH combined with sorafenib effectively inhibited tumor development and progression, including intrahepatic, pulmonary, and splenic metastases. Targeting ASPH generated antitumor efficacy will pave the way for HCC therapy.

Keywords:  Aspartate β-hydroxylase; Hepatocellular carcinoma; Metastasis; Sorafenib

DOI:  https://doi.org/10.1016/j.canlet.2024.217396
Eur J Pharmacol. 2024 Dec 24. pii: S0014-2999(24)00921-X. [Epub ahead of print] 177231

Vodobatinib overcomes cancer multidrug resistance by attenuating the drug efflux function of ABCB1 and ABCG2.

Yen-Ching Li, Bing-Huan Lin, Megumi Murakami, Yu-Shan Wu, Tai-Ho Hung, Chin-Chuan Chen, Suresh V Ambudkar, Chung-Pu Wu.

  Multidrug resistance (MDR) remains a significant obstacle in cancer treatment, primarily attributable to the overexpression of ATP-binding cassette (ABC) transporters such as ABCB1 and ABCG2 within cancer cells. These transporters actively diminish the effectiveness of cytotoxic drugs by facilitating ATP hydrolysis-dependent drug efflux, thereby reducing intracellular drug accumulation. Given the absence of approved treatments for multidrug-resistant cancers and the established benefits of combining tyrosine kinase inhibitors (TKIs) with conventional anticancer drugs, we investigate the potential of vodobatinib, a potent c-Abl TKI presently in clinical trials, to restore sensitivity to chemotherapeutic agents in multidrug-resistant cancer cells overexpressing ABCB1 and ABCG2. Results indicate that vodobatinib, administered at sub-toxic concentrations, effectively restores the sensitivity of multidrug-resistant cancer cells to cytotoxic drugs in a concentration-dependent manner. Moreover, vodobatinib enhances drug-induced apoptosis in these cells by inhibiting the drug-efflux function of ABCB1 and ABCG2, while maintaining their expression levels. Moreover, we found that while vodobatinib enhances the ATPase activity of ABCB1 and ABCG2, the overexpression of these transporters does not induce resistance to vodobatinib. These results strongly suggest that increased levels of ABCB1 or ABCG2 are unlikely to play a significant role in the development of resistance to vodobatinib in cancer patients. Overall, our findings unveil an additional pharmacological facet of vodobatinib against ABCB1 and ABCG2 activity, suggesting its potential incorporation into combination therapy for a specific subset of patients with tumors characterized by high ABCB1 or ABCG2 levels. Further investigation is warranted to fully elucidate the clinical implications of this therapeutic approach.

Keywords:  ABCB1; ABCG2; Drug repositioning; Multidrug resistance; Vodobatinib

DOI:  https://doi.org/10.1016/j.ejphar.2024.177231
medRxiv. 2024 Dec 13. pii: 2024.12.12.24318845. [Epub ahead of print]

Androgen receptor drives polyamine synthesis creating a vulnerability for prostate cancer.

Rajendra Kumar, Sheila Jonnatan, David E Sanin, Varsha Vakkala, Anoushka Kadam, Shivani Kumar, Susan L Dalrymple, Liang Zhao, Jackson Foley, Cassandra E Holbert, Ashley Nwafor, Srushti Kittane, Elizabeth Penner, Petya Apostolova, Samuel Warner, Chi V Dang, Eneda Toska, Elizabeth A Thompson, John T Isaacs, Angelo M De Marzo, Erika L Pearce, Tracy Murray Stewart, Robert A Casero, Samuel R Denmeade, Laura A Sena.

Supraphysiological androgen (SPA) treatment can paradoxically restrict growth of castration-resistant prostate cancer with high androgen receptor (AR) activity, which is the basis for use of Bipolar Androgen Therapy (BAT) for patients with this disease. While androgens are widely appreciated to enhance anabolic metabolism, how SPA-mediated metabolic changes alter prostate cancer progression and therapy response is unknown. Here, we report that SPA markedly increased intracellular and secreted polyamines in prostate cancer models. This occurred through AR binding at enhancer sites upstream of the ODC1 promoter to increase abundance of ornithine decarboxylase (ODC), a rate-limiting enzyme of polyamine synthesis, and de novo synthesis of polyamines from arginine. SPA-stimulated polyamines enhance prostate cancer fitness, as dCas9-KRAB-mediated inhibition of AR regulation of ODC1 or direct ODC inhibition by difluoromethylornithine (DFMO) increased efficacy of SPA. Mechanistically, this occurred in part due to increased activity of S-adenosylmethionine decarboxylase 1 (AMD1), which was stimulated both by AR and by loss of negative feedback by polyamines, leading to depletion of its substrate S-adenosylmethionine and global protein methylation. These data provided the rationale for a clinical trial testing the safety and efficacy of BAT in combination with DFMO for patients with metastatic castration-resistant prostate cancer. Pharmacodynamic studies of this drug combination in the first five patients on trial indicated that the drug combination resulted in effective polyamine depletion in plasma. Thus, the AR potently stimulates polyamine synthesis, which constitutes a vulnerability in prostate cancer treated with SPA that can be targeted therapeutically.

DOI: https://doi.org/10.1101/2024.12.12.24318845
bioRxiv. 2024 Nov 22. pii: 2024.11.20.624567. [Epub ahead of print]

Metabolic Adaptations To Acute Glucose Uptake Inhibition Converge Upon Mitochondrial Respiration For Leukemia Cell Survival.

Monika Komza, Jesminara Khatun, Jesse D Gelles, Andrew P Trotta, Ioana Abraham-Enachescu, Juan Henao, Ahmed Elsaadi, Andriana G Kotini, Cara Clementelli, JoAnn Arandela, Sebastian El Ghaity-Beckley, Agneesh Barua, Yiyang Chen, Bridget K Marcellino, Eirini P Papapetrou, Masha V Poyurovsky, Jerry Edward Chipuk.

One hallmark of cancer is the upregulation and dependency on glucose metabolism to fuel macromolecule biosynthesis and rapid proliferation. Despite significant pre-clinical effort to exploit this pathway, additional mechanistic insights are necessary to prioritize the diversity of metabolic adaptations upon acute loss of glucose metabolism. Here, we investigated a potent small molecule inhibitor to Class I glucose transporters, KL-11743, using glycolytic leukemia cell lines and patient-based model systems. Our results reveal that while several metabolic adaptations occur in response to acute glucose uptake inhibition, the most critical is increased mitochondrial oxidative phosphorylation. KL-11743 treatment efficiently blocks the majority of glucose uptake and glycolysis, yet markedly increases mitochondrial respiration via enhanced Complex I function. Compared to partial glucose uptake inhibition, dependency on mitochondrial respiration is less apparent suggesting robust blockage of glucose uptake is essential to create a metabolic vulnerability. When wild-type and oncogenic RAS patient-derived induced pluripotent stem cell acute myeloid leukemia (AML) models were examined, KL-11743 mediated induction of mitochondrial respiration and dependency for survival associated with oncogenic RAS. Furthermore, we examined the therapeutic potential of these observations by treating a cohort of primary AML patient samples with KL-11743 and witnessed similar dependency on mitochondrial respiration for sustained cellular survival. Together, these data highlight conserved adaptations to acute glucose uptake inhibition in diverse leukemic models and AML patient samples, and position mitochondrial respiration as a key determinant of treatment success.

DOI: https://doi.org/10.1101/2024.11.20.624567
Metabolites. 2024 Nov 21. pii: 648. [Epub ahead of print]14(12):

Singlet Oxygen-Induced Mitochondrial Reset in Cancer: A Novel Approach for Ovarian Cancer Therapy.

Jorgelindo da Veiga Moreira, Laurent Schwartz, Mario Jolicoeur.

  Background/Objectives: This study explores the generation of singlet oxygen (SO) through methylene blue (MB) activation as a metabolic intervention for ovarian cancer. We aimed to examine the role of SO in modulating mitochondrial function, cellular metabolism, and proliferation in ovarian cancer cell lines compared to control cells. Methods: The study utilized two ovarian cancer cell lines, OV1369-R2 and TOV1369, along with ARPE-19 control cells. Following MB treatment and light activation, mitochondrial function and ATP synthesis were assessed. Metabolomic analyses were performed to evaluate changes in central carbon metabolism, particularly focusing on markers of the Warburg effect. Results: TOV1369 cells exhibited a pronounced sensitivity to MB treatment, resulting in significant inhibition of ATP synthesis and reduced proliferation. Metabolomic analysis indicated that MB-induced SO production partially reversed the Warburg effect, suggesting a shift from glycolysis to oxidative phosphorylation. These effects were less pronounced in OV1369-R2 and ARPE-19 cells, correlating with their lower MB sensitivity. Conclusions: MB-generated SO selectively modulates mitochondrial energetics in ovarian cancer cells, driving a metabolic reorganization that curtails their proliferative capacity. This approach, leveraging the bacterial-like features of cancer metabolism, offers a promising therapeutic avenue to induce apoptosis and enhance treatment outcomes in ovarian cancer.

Keywords:  metabolic bistability; methylene blue; mitochondrial involution; ovarian cancer; singlet oxygen

DOI:  https://doi.org/10.3390/metabo14120648
Free Radic Biol Med. 2024 Dec 24. pii: S0891-5849(24)01154-7. [Epub ahead of print]

Nonthermal Plasma Boosted Dichloroacetate Induces Metabolic Shifts to Combat Glioblastoma CSCs via Oxidative Stress.

Apurva Jaiswal, Neha Kaushik, Paritosh Patel, Tirtha Raj Acharya, Subhadip Mukherjee, Eun Ha Choi, Nagendra Kumar Kaushik.

  Glioblastoma (GBM) remains a formidable clinical challenge, with cancer stem cells (CSCs) contributing to treatment resistance and tumor recurrence. Conventional treatments often fail to eradicate these CSCs characterized by enhanced resistance to standard therapies through metabolic plasticity making them key targets for novel treatment approaches. Addressing this challenge, this study introduces a novel combination therapy of dichloroacetate (DCA), a metabolic modulator and nonthermal plasma to induce oxidative stress in glioblastomas. Our results demonstrate that DCA and nonthermal plasma (NTP) synergistically increase ROS production, resulting in endoplasmic reticulum (ER) stress and mitochondrial reprogramming, key factors in the initiation of programmed cell death. Furthermore, the combination downregulated key stemness markers indicating effective CSCs suppression. Upregulation of pro-apoptotic proteins and downregulation of anti-apoptotic factors highlight the induction of apoptosis in glioma cells. This study provides compelling evidence that the combination of DCA and NTP offers a novel and effective strategy for targeting glioma CSCs by inducing oxidative and metabolic stress, underscoring potential therapeutic advancements in glioblastoma treatment.

Keywords:  Glioblastoma (GBM); apoptosis; cancer stem cells (CSCs); metabolic reprogramming; nonthermal plasma (NTP); oxidative stress

DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.12.045
J Exp Clin Cancer Res. 2024 Dec 26. 43(1): 330

OTULIN confers cisplatin resistance in osteosarcoma by mediating GPX4 protein homeostasis to evade the mitochondrial apoptotic pathway.

Zehang Zheng, Yunhao Zeng, Xing Bao, Chuang Huang, Fengjing Guo, Fei Xu, Zhengqiang Luo.

   BACKGROUND: Osteosarcoma (OS), the most prevalent primary malignant bone tumor in children and adolescents, arises from bone-forming mesenchymal cells. Despite advancements in surgical resection and neoadjuvant chemotherapy (cisplatin, doxorubicin, and methotrexate), chemotherapy resistance remains a significant challenge, leading to poor survival rates in patients with metastatic or recurrent OS.
METHODS: In this study, we focused on the role of OTULIN, a key linear deubiquitinating enzyme, in OS chemoresistance. In addition, mechanistic investigations were carried out to identify potential downstream targets of OTULIN involved in cisplatin resistance.
RESULTS: Our results demonstrated that OTULIN expression was significantly upregulated in OS tissues and cell lines following cisplatin treatment but not in response to doxorubicin or methotrexate. High OTULIN expression was associated with reduced survival in sarcoma patients. Furthermore, immunohistochemical analysis of prechemotherapy and postchemotherapy OS tissues revealed increased OTULIN expression in postchemotherapy samples. In vitro results demonstrated that OTULIN plays a critical role in mediating cisplatin resistance in OS. Mechanistically, GPX4 could be a downstream target of OTULIN, conferring cisplatin resistance to OS by blocking the mitochondrial apoptotic pathway but not ferroptosis. Specifically, OTULIN prevents the proteasomal degradation of GPX4 by reducing its ubiquitin level, thereby conferring resistance to cisplatin in OS cells.
CONCLUSION: This study highlights the importance of OTULIN in OS chemoresistance and provides a promising approach for targeting the OTULIN-GPX4 axis to improve the prognosis of OS patients. Our findings offer new insights into the molecular mechanisms underlying OS chemoresistance and suggest potential therapeutic targets for future clinical interventions.

Keywords:  Apoptosis; Chemoresistance; GPX4; OTULIN; Osteosarcoma

DOI:  https://doi.org/10.1186/s13046-024-03249-8
Aging Cell. 2024 Dec 27. e14462

Effects of Aging on Glucose and Lipid Metabolism in Mice.

Evan C Lien, Ngoc Vu, Anna M Westermark, Laura V Danai, Allison N Lau, Yetiş Gültekin, Matthew A Kukurugya, Bryson D Bennett, Matthew G Vander Heiden.

  Aging is accompanied by multiple molecular changes that contribute to aging associated pathologies, such as accumulation of cellular damage and mitochondrial dysfunction. Tissue metabolism can also change with age, in part, because mitochondria are central to cellular metabolism. Moreover, the cofactor NAD+, which is reported to decline across multiple tissues during aging, plays a central role in metabolic pathways such as glycolysis, the tricarboxylic acid cycle, and the oxidative synthesis of nucleotides, amino acids, and lipids. To further characterize how tissue metabolism changes with age, we intravenously infused [U-13C]-glucose into young and old C57BL/6J, WSB/EiJ, and diversity outbred mice to trace glucose fate into downstream metabolites within plasma, liver, gastrocnemius muscle, and brain tissues. We found that glucose incorporation into central carbon and amino acid metabolism was robust during healthy aging across these different strains of mice. We also observed that levels of NAD+, NADH, and the NAD+/NADH ratio were unchanged in these tissues with healthy aging. However, aging tissues, particularly brain, exhibited evidence of upregulated fatty acid and sphingolipid metabolism reactions that regenerate NAD+ from NADH. These data suggest that NAD+-generating lipid metabolism reactions may help to maintain the NAD+/NADH ratio during healthy aging.

Keywords:  NAD; aging; metabolic rate; mice

DOI:  https://doi.org/10.1111/acel.14462
Cancer Commun (Lond). 2024 Dec 25.

Orchestrated desaturation reprogramming from stearoyl-CoA desaturase to fatty acid desaturase 2 in cancer epithelial-mesenchymal transition and metastasis.

Zhicong Chen, Yanqing Gong, Fukai Chen, Hyeon Jeong Lee, Jinqin Qian, Jing Zhao, Wenpeng Zhang, Yamin Li, Yihui Zhou, Qiaobing Xu, Yu Xia, Liqun Zhou, Ji-Xin Cheng.

   BACKGROUND: Adaptative desaturation in fatty acid (FA) is an emerging hallmark of cancer metabolic plasticity. Desaturases such as stearoyl-CoA desaturase (SCD) and fatty acid desaturase 2 (FADS2) have been implicated in multiple cancers, and their dominant and compensatory effects have recently been highlighted. However, how tumors initiate and sustain their self-sufficient FA desaturation to maintain phenotypic transition remains elusive. This study aimed to explore the molecular orchestration of SCD and FADS2 and their specific reprogramming mechanisms in response to cancer progression.
METHODS: The potential interactions between SCD and FADS2 were explored by bioinformatics analyses across multiple cancer cohorts, which guided subsequent functional and mechanistic investigations. The expression levels of desaturases were investigated with online datasets and validated in both cancer tissues and cell lines. Specific desaturation activities were characterized through various isomer-resolved lipidomics methods and sensitivity assays using desaturase inhibitors. In-situ lipid profiling was conducted using multiplex stimulated Raman scattering imaging. Functional assays were performed both in vitro and in vivo, with RNA-sequencing employed for the mechanism verification.
RESULTS: After integration of the RNA-protein-metabolite levels, the data revealed that a reprogramming from SCD-dependent to FADS2-dependent desaturation was linked to cancer epithelial-mesenchymal transition (EMT) and progression in both patients and cell lines. FADS2 overexpression and SCD suppression concurrently maintained EMT plasticity. A FADS2/β-catenin self-reinforcing feedback loop facilitated the degree of lipid unsaturation, membrane fluidity, metastatic potential and EMT signaling. Moreover, SCD inhibition triggered a lethal apoptosis but boosted survival plasticity by inducing EMT and enhancing FA uptake via adenosine monophosphate-activated protein kinase activation. Notably, this desaturation reprogramming increased transforming growth factor-β2, effectively sustaining aggressive phenotypes and metabolic plasticity during EMT.
CONCLUSIONS: These findings revealed a metabolic reprogramming from SCD-dependent to FADS2-dependent desaturation during cancer EMT and progression, which concurrently supports EMT plasticity. Targeting desaturation reprogramming represents a potential vulnerability for cancer metabolic therapy.

Keywords:  cancer metastasis; epithelial‐mesenchymal transition; fatty acid desaturase 2; metabolic reprogramming; stearoyl‐CoA desaturase

DOI:  https://doi.org/10.1002/cac2.12644
Transl Oncol. 2024 Dec 20. pii: S1936-5233(24)00376-0. [Epub ahead of print]52 102250

ANGPTL3 overcomes sorafenib resistance via suppression of SNAI1 and CPT1A in liver cancer.

Yang-Hsiang Lin, Cheng-Yi Chen, Hsiang-Cheng Chi, Meng-Han Wu, Ming-Wei Lai, Chau-Ting Yeh.

  Liver cancer, encompassing hepatocellular carcinoma (HCC) and hepatoblastoma, the latter of which primarily occurs in early childhood, is the most common malignant tumor arising from liver and is responsible for a significant number of cancer-related deaths worldwide. Targeted drugs have been used for anti-liver cancer treatment in the advanced stage, while their efficacy is greatly compromised by development of drug resistance. Drug resistance is a complicated process regulated by intrinsic and extrinsic signals and has been associated with poorer prognosis in cancer patients. In the current study, online available dataset analysis uncovered that angiopoietin-like protein 3 (ANGPTL3) manifested lower expression in sorafenib-resistant liver cancer cell lines. Additionally, ANGPTL3 was downregulated in HCC tissues, with its expression positively correlated with good prognosis. Functionally, ectopic expression of ANGPTL3 re-sensitized sorafenib-resistant cells, enhancing the sorafenib-induced reduction in cell viability and migration by suppressing zinc finger protein SNAI1 (SNAI1) expression and the protein stability of carnitine O-palmitoyltransferase 1, liver isoform (CPT1A). Clinical correlation analysis revealed that ANGPTL3 was negatively associated with SNAI1 expression. In conclusion, we identify a novel association between ANGPTL3, SNAI1 and CPT1A on sorafenib therapeutic response. Targeting ANGPTL3/SNAI1/CPT1A axis may serve as a therapeutic approach to improve prognosis of liver cancer patients with sorafenib resistance.

Keywords:  ANGPTL3; CPT1A; Hepatocellular carcinoma; Protein stability; sorafenib

DOI:  https://doi.org/10.1016/j.tranon.2024.102250
Cell Commun Signal. 2024 Dec 20. 22(1): 613

V-ATPase in cancer: mechanistic insights and therapeutic potentials.

Tingting Chen, Xiaotan Lin, Shuo Lu, Bo Li.

  Vacuolar-type H+-ATPase (V-ATPase) is a crucial proton pump that plays an essential role in maintaining intracellular pH homeostasis and a variety of physiological processes. This review provides an in-depth exploration of the structural components, functional mechanisms, and regulatory modes of V-ATPase in cancer cells. Comprising two main domains, V1 and V0, V-ATPase drives the proton pump through ATP hydrolysis, sustaining the pH balance within the cell and organelles. In cancer cells, the enhanced activity of V-ATPase is closely associated with the proliferation and metastasis of tumor cells, and it promotes the growth and invasion of tumor cells by regulating pH values in the tumor microenvironment. Moreover, the interaction between V-ATPase and key metabolic regulatory factors, the mechanistic target of rapamycin complex 1 (mTORC1) and AMP-activated protein kinase (AMPK), impacts the metabolic state of cancer cells. The role of V-ATPase in tumor drug resistance and its regulatory mechanism in non-canonical autophagy offer new perspectives and potential targets for cancer therapy. Future research directions will focus on the specific mechanisms of action of V-ATPase in the tumor microenvironment and how to translate its inhibitors into clinical applications, providing significant scientific evidence for the development of new therapeutic strategies.

Keywords:  Proton pump; Therapeutic targets; V-ATPase; pH homeostasis

DOI:  https://doi.org/10.1186/s12964-024-01998-9
Mol Metab. 2024 Dec 18. pii: S2212-8778(24)00216-3. [Epub ahead of print] 102085

Synthetic inhibition of SREBP2 and the mevalonate pathway blocks rhabdomyosarcoma tumor growth in vitro and in vivo and promotes chemosensitization.

Silvia Codenotti, Michela Asperti, Maura Poli, Luisa Lorenzi, Alberto Pietrantoni, Matteo Cassandri, Francesco Marampon, Alessandro Fanzani.

  By analyzing RNA datasets from rhabdomyosarcoma (RMS), a soft tissue tumor with a prevalence in young people, we found upregulation of sterol regulatory element-binding protein 2 (SREBP2) and mevalonate pathway (MVP) genes, including 3-Hydroxy-3-Methylglutaryl-CoA Reductase (HMGCR), farnesyl-diphosphate synthase (FDPS), squalene epoxidase (SQLE), which correlated with worse overall patient survival and predicted statin sensitivity. In human RD and RH30 lines, treatment with 0.01-1 μM doses of fatostatin (SREBP2 inhibitor), lovastatin and simvastatin (HMGCR inhibitors), and zoledronic acid (FDPS inhibitor) impaired cell growth and migration, which were conversely stimulated by 50-100 μM cholesterol (CHO) supplementation. Treatment of RMS lines with higher doses of SREBP2 and MVP inhibitors (5-50 μM) promoted oxidative cell death and chemosensitization in combination with actinomycin D. Administration of lovastatin or fatostatin to RD and RH30 cells produced a rapid attenuation of Erk1/2 and Akt1 phosphorylation, detectable after 4 h of treatment. Furthermore, tumor mass growth of xenografted RD cells in NOD/SCID mice was reduced by oral administration of lovastatin. Lastly, we found the forced Akt1 activation in RD cells was sufficient to drive SREBP2, HMGCR and SQLE protein expression and enhance cell death susceptibility to MVP inhibitors. Taken together, these data suggest that the axis formed by Akt1, SREBP2 and MVP is critical for RMS tumor growth, migration, and oxidative stress protection mainly through the maintenance of CHO levels that ensure proper intracellular signaling. Therefore, targeting CHO levels by SREBP2 and MVP inhibition may represent a viable option to improve the combination therapy protocol in RMS.

Keywords:  Chemoresistance; Cholesterol; Mevalonate pathway; Oxidative stress; Rhabdomyosarcoma

DOI:  https://doi.org/10.1016/j.molmet.2024.102085
J Transl Med. 2024 Dec 20. 22(1): 1125

Napabucasin-loaded PLGA nanoparticles trigger anti-HCC immune responses by metabolic reprogramming of tumor-associated macrophages.

Zhenwei Song, Hongfei Chen, Xueyao Wang, Zhiyue Zhang, Hui Li, Huajun Zhao, Yang Liu, Qiuju Han, Jian Zhang.

   BACKGROUND: JAK/STAT3 is one of the critical signaling pathways involved in the occurrence and development of hepatocellular carcinoma (HCC). BBI608 (Napabucasin), as a novel small molecule inhibitor of STAT3, has shown previously excellent anti-HCC effects in vitro and in mouse models. However, low bioavailability, high cytotoxicity and other shortcomings limit its clinical application. In this study, PLGA was selected to prepare Napabucasin PLGA nanoparticles (NPs) by solvent evaporation method, overcoming these limitations and improving the passive targeting effect that nanoparticle mediated. Base on this, we systematically evaluated the anti-HCC effect of Napabucasin-PLGA NPs and explored the underlying mechanisms.
METHODS: Napabucasin-PLGA NPs were prepared by solvent evaporation method. CCK-8 assay, Annexin V/PI double staining, RT-qPCR, colony formation assay, and Western blotting were performed to evaluate the anti-HCC effect of Napabucasin-PLGA NPs in vitro. Proliferation assay and migration assay were used to detect the effects of Napabucasin-PLGA NPs-treated HCC-TAMs on tumor biological characteristics of HCC cells. Flow cytometry was used to detect anti-HCC immune responses induced by Napabucasin-PLGA NPs in vivo.
RESULTS: Our results demonstrated that Napabucasin-PLGA NPs could improve the bioavailability of Napabucasin and enhance Napabucasin-mediated the anti-HCC effects in vitro and in vivo with no significant drug toxicity. In addition to the direct inhibitory effects on the tumor biological characteristics of HCC cells, Napabucasin-PLGA NPs could promote the polarization of macrophages from tumor-promoting M2-type to anti-tumor M1-type, improving the tumor immune microenvironment and augmenting T cell-mediated anti-tumor responses. The underlining mechanisms showed Napabucasin-PLGA NPs suppressed the STAT3/FAO signaling axis in HCC-induced tumor-associated macrophages (TAMs).
CONCLUSIONS: These findings demonstrated Napabucasin-PLGA NPs is a potential therapeutic candidate for HCC, and provided a new theoretical and experimental basis for further development and clinical application of Napabucasin.

Keywords:  FAO; Nanoparticles; Napabucasin; STAT3; TAMs

DOI:  https://doi.org/10.1186/s12967-024-05917-x