bims-meract Biomed News
on Metabolic reprogramming and anti-cancer therapy
Issue of 2025–05–25
eighteen papers selected by
Andrea Morandi, Università degli Studi di Firenze
  1. GLS1 promotes lipid metabolism in hepatocellular carcinoma by regulating the PI3K/AKT/mTORC1 signaling pathway through SREBP-1.
  2. GPT2 mediates metabolic alterations in platinum-resistant ovarian cancer cells.
  3. DHA suppresses hormone-sensitive and castration-resistant prostate cancer growth by decreasing de novo lipogenesis.
  4. Sphingolipid synthesis in tumor-associated macrophages confers immunotherapy resistance in hepatocellular carcinoma.
  5. Mitochondrial fission factor drives an actionable metabolic vulnerability in multiple myeloma.
  6. Histone methyltransferase ASH1L primes metastases and metabolic reprogramming of macrophages in the bone niche.
  7. Gnetin C sensitizes darolutamide-resistant prostate cancer cells by targeting NAD+ and energy metabolism.
  8. From genes to therapy: a lipid Metabolism-Related genetic risk model predicts HCC outcomes and enhances immunotherapy.
  9. Isocitrate dehydrogenase 1 primes group-3 medulloblastomas for cuproptosis.
  10. Ketogenesis instigates immune suppression in enzalutamide resistant prostate cancer via OTUD7B β-hydroxybutyrylation.
  11. The HNRNPC/CELF2 signaling pathway drives glycolytic reprogramming and mitochondrial dysfunction in drug-resistant acute myeloid leukemia.
  12. High-protein diets alleviate tumour growth and drug resistance by promoting AKT aggregation and turnover.
  13. Role of fructose in renal cell carcinoma progression.
  14. Targeting SLC7A11 with sorafenib sensitizes stereotactic body radiotherapy in colorectal cancer liver metastasis.
  15. Metformin reverses 5-FU resistance induced by radiotherapy through mediating folate metabolism in colorectal cancer.
  16. Recharacterization of the Tumor Suppressive Mechanism of RSL3 Identifies the Selenoproteome as a Druggable Pathway in Colorectal Cancer.
  17. CD44 and SLC1A2 are commonly regulated but do not form a fusion transcript in ER+ breast cancer.
  18. FUT8 Is a Critical Driver of Prostate Tumour Growth and Can Be Targeted Using Fucosylation Inhibitors.
  1. Am J Transl Res. 2025 ;17(4): 2527-2540
    GLS1 promotes lipid metabolism in hepatocellular carcinoma by regulating the PI3K/AKT/mTORC1 signaling pathway through SREBP-1.
    Yaocheng Sun, Ying Shen, Yongmin Yan, Wei Luo, Chuanlei Liu, Jianjun Tang.
       OBJECTIVES: Cancer cells exhibit altered metabolic profiles. Glutaminase 1 (GLS1), a key enzyme in cancer cells, promoting glutamine catabolism to glutamate and ammonia, is strongly associated with various human malignancies.
    METHODS: GLS1 promotes lipid accumulation and cell proliferation by upregulating the expression of sterol regulatory element-binding protein 1 (SREBP-1) and SREBP cleavage-activating protein (SCAP). Mechanistically, GLS1 promotes lipid metabolism in HCC cells through the activation of the PI3K/AKT/mTORC pathway.
    RESULTS: GLS1's role in lipid metabolism in hepatocellular carcinoma (HCC) remains unexplored. Our findings indicate that GLS1 is not only significantly overexpressed in HCC but also negatively correlates with clinical prognosis. Further investigation revealed that GLS1 drives lipid accumulation and de novo fatty acid synthesis in HCC.
    CONCLUSIONS: Our study suggests that GLS1 mediates SREBP-1 to drive lipid metabolism in HCC via the phosphatidylinositol-3-kinase/protein kinase B/mammalian target of rapamycin complex 1 (PI3K/AKT/mTORC1) signaling pathway, thus we present GLS1 as a potential biomarker and therapeutic target for HCC.
    Keywords:  GLS1; Hepatocellular carcinoma; PI3K/AKT/mTORC1 signaling pathway; SREBP-1; lipid metabolism
    DOI:  https://doi.org/10.62347/ZTGP5030
  2. Res Sq. 2025 May 09. pii: rs.3.rs-6480518. [Epub ahead of print]
    GPT2 mediates metabolic alterations in platinum-resistant ovarian cancer cells.
    Adriana Ponton-Almodovar, Mary Priyanka Udumula, Vrinda Khullar, Faraz Rashid, Ramandeep Rattan, Jamie J Bernard, Sachi Horibata.
      Metabolic reprogramming is recognized as a hallmark of cancer frequently associated with drug resistance in ovarian cancer. This is problematic as ovarian cancer is one of the deadliest gynecologic cancers with platinum resistance contributing to poor survival. However, the mechanism by which ovarian cancer cell metabolism contributes to platinum resistance is not well understood. Herein, metabolic signatures were determined in platinum-resistant ovarian cancer cell lines compared to the more platinum-sensitive parental lines. Chemoresistant ovarian cancer cells showed increased oxidative phosphorylation (OXPHOS) compared to chemosensitive cells. This was associated with elevated levels of glutaminolysis and tricarboxylic acid (TCA)-related metabolites supporting their dependence on OXPHOS. Key enzymes involved in glutaminolysis, specifically, glutamic-pyruvic transaminase 2 (GPT2), were upregulated in chemoresistant compared to chemosensitive cells. Interestingly, high GPT2 gene expression is associated with worse prognosis in ovarian cancer patients, adding translational relevance to the pre-clinical findings. GPT2 knockout in chemoresistant cells restored the metabolic phenotype to that of the sensitive cells and reversed drug resistance. These data suggest that GPT2 is a critical link between glutaminolysis, the TCA cycle, and OXPHOS and is a potential target to attenuate the increased metabolic activity associated with a chemoresistant phenotype.
    Keywords:  GPT2; glutamine; metabolism; ovarian cancer
    DOI:  https://doi.org/10.21203/rs.3.rs-6480518/v1
  3. Biochim Biophys Acta Mol Cell Biol Lipids. 2025 May 16. pii: S1388-1981(25)00042-3. [Epub ahead of print] 159634
    DHA suppresses hormone-sensitive and castration-resistant prostate cancer growth by decreasing de novo lipogenesis.
    G H Tamarindo, C F Ribeiro, S Rodrigues, R M Góes, M Loda.
       OBJECTIVE: De novo lipogenesis (DNL) is associated with prostate cancer (PCa) progression, while fatty acid synthase (FASN) overexpression is a hallmark of DNL. Palmitate, its main product, is a saturated fatty acid that supports PCa growth. Polyunsaturated fatty acids (PUFAs), which can be acquired from the microenvironment, undergo peroxidation more readily and affect membrane fluidity. Docosahexaenoic acid (DHA) is a prototype PUFA omega-3 produced inefficiently in human cells. Its levels are low in PCa cells compared to normal cells. We hypothesize that excess DHA may reprogram lipid metabolism and induce cell growth suppression.
    METHODS: Androgen-responsive LNCaP, castration-resistant cells C4-2 and 22Rv1, human PCa castration-resistant organoids, and prostate cancer xenografts were exposed to DHA.
    RESULTS: DHA accumulated into lipid droplets as triacylglycerols and cholesterol esters, led to increased phospholipid acyl chain unsaturation and altered phospholipid ratio, a known trigger of endoplasmic reticulum (ER) stress. DHA caused a decrease in sterol regulatory element-binding protein (SREBP) transcriptional program, which, in turn, led to decreased expression of FASN. The subsequent reduction in DNL caused downregulation of the androgen receptor (AR) and its splice variant AR-V7. In addition, β-oxidation was enhanced, and DHA was preferentially oxidized over palmitate. Glucose oxidation also increased in the presence of DHA. Finally, DHA led to ROS overproduction, oxidative damage, and ER stress.
    CONCLUSIONS: DHA reduces the growth of hormone-sensitive and castration-resistant PCa both in vitro and in vivo via deregulation of lipid metabolism.
    Keywords:  DHA; Omega-3; Prostate cancer;lipids
    DOI:  https://doi.org/10.1016/j.bbalip.2025.159634
  4. Sci Adv. 2025 May 23. 11(21): eadv0558
    Sphingolipid synthesis in tumor-associated macrophages confers immunotherapy resistance in hepatocellular carcinoma.
    Xiaozhen Zhang, Mengyi Lao, Kang Sun, Hanshen Yang, Lihong He, Xinyuan Liu, Linyue Liu, Sirui Zhang, Chengxiang Guo, Sicheng Wang, Jiatao Shi, Xiaoyu Zhang, Daqian Xu, Xiongbin Lu, Xueli Bai, Tingbo Liang.
      Dysregulated metabolism of immune cells in the tumor microenvironment leads to immune evasion and tumor progression. As a major cell component in the tumor, the metabolic reprogramming of tumor-associated macrophages (TAMs) creates an immunosuppressive microenvironment in hepatocellular carcinoma (HCC). Our study found that sphingolipid (particularly, sphingosine-1-phosphate or S1P) levels are a clinical indicator for prognosis and immunotherapy response in patients with HCC. S1P primarily derived from TAMs, where NIMA-related kinase 2 (NEK2) plays a key role in controlling the activity of serine palmitoyl-CoA transferase, a rate-limiting enzyme in S1P biosynthesis. The S1P produced by NEK2hi TAMs promotes hepatic tumor progression and confers immunotherapy resistance. Targeting S1P synthesis with a NEK2 inhibitor or S1P antagonist disrupted the immunosuppressive function of macrophages, shifted regulatory T cells (Tregs) to TH17 cells, and increased the number and activity of tumor-infiltrating T effectors, thereby enhancing antitumor efficacy in synergy with immune checkpoint blockade therapy.
    DOI:  https://doi.org/10.1126/sciadv.adv0558
  5. Haematologica. 2025 May 22.
    Mitochondrial fission factor drives an actionable metabolic vulnerability in multiple myeloma.
    Maria Eugenia Gallo Cantafio, Ilenia Valentino, Roberta Torcasio, Ludovica Ganino, Claudia Veneziano, Pierpaolo Murfone, Maria Mesuraca, Ida Perrotta, Federico Tallarigo, Valter Agosti, Carmela De Marco, Teresa Pasqua, Cesarina Giallongo, Anna Rita Cappello, Marco Fiorillo, Massimo Gentile, Daniele Tibullo, Giuseppe Viglietto, Antonino Neri, Nicola Amodio.
      Proliferating multiple myeloma (MM) cells in the bone marrow fluctuate across various metabolic states to resist cancer treatments. Herein, we investigate how mitochondrial dynamics, which controls mitochondrial fitness via coordinated fission and fusion events, shapes MM cell metabolism impacting growth, survival and drug sensitivity. We identify MFF (Mitochondrial Fission Factor), a pivotal driver of mitochondrial fragmentation, as being highly expressed in MM plasma cells bearing cytogenetic abnormalities predicting poor clinical outcome. In preclinical models, MFF selective inhibition via multiple RNAbased strategies (shRNAs, siRNAs or LNA gapmeR ASOs) reduces MM cell growth both in vitro and in vivo, enabling adaptive metabolic responses consistent with the induction of glycolysis and the inhibition of lactate-mediated OXPHOS. We also demonstrate that lactate supplementation, as well as clinically relevant drugs promoting lactate accumulation, such as AZD3965 and Syrosingopine, trigger MFF-dependent metabolic changes, enhancing the sensitivity of MM cells to strategies targeting mitochondrial fission. Finally, we highlight a novel lactate-MFF axis involved in proteasome inhibitor resistance, and show that combining AZD3965 or Syrosingopine with bortezomib results in synergistic anti-MM activity along with MFF down-regulation. Collectively, these data point to MFF-dependent mitochondrial fragmentation as a key metabolic hallmark of MM, providing a framework for the development of novel therapeutic strategies targeting mitochondrial dynamics and harnessing the metabolic plasticity of malignant plasma cells.
    DOI:  https://doi.org/10.3324/haematol.2025.287526
  6. Nat Commun. 2025 May 20. 16(1): 4681
    Histone methyltransferase ASH1L primes metastases and metabolic reprogramming of macrophages in the bone niche.
    Chenling Meng, Kevin Lin, Wei Shi, Hongqi Teng, Xinhai Wan, Anna DeBruine, Yin Wang, Xin Liang, Javier Leo, Feiyu Chen, Qianlin Gu, Jie Zhang, Vivien Van, Kiersten L Maldonado, Boyi Gan, Li Ma, Yue Lu, Di Zhao.
      Bone metastasis is a major cause of cancer death; however, the epigenetic determinants driving this process remain elusive. Here, we report that histone methyltransferase ASH1L is genetically amplified and is required for bone metastasis in men with prostate cancer. ASH1L rewires histone methylations and cooperates with HIF-1α to induce pro-metastatic transcriptome in invading cancer cells, resulting in monocyte differentiation into lipid-associated macrophage (LA-TAM) and enhancing their pro-tumoral phenotype in the metastatic bone niche. We identified IGF-2 as a direct target of ASH1L/HIF-1α and mediates LA-TAMs' differentiation and phenotypic changes by reprogramming oxidative phosphorylation. Pharmacologic inhibition of the ASH1L-HIF-1α-macrophages axis elicits robust anti-metastasis responses in preclinical models. Our study demonstrates epigenetic alterations in cancer cells reprogram metabolism and features of myeloid components, facilitating metastatic outgrowth. It establishes ASH1L as an epigenetic driver priming metastasis and macrophage plasticity in the bone niche, providing a bona fide therapeutic target in metastatic malignancies.
    DOI:  https://doi.org/10.1038/s41467-025-59381-2
  7. Biochem Biophys Res Commun. 2025 May 14. pii: S0006-291X(25)00723-5. [Epub ahead of print]770 152009
    Gnetin C sensitizes darolutamide-resistant prostate cancer cells by targeting NAD+ and energy metabolism.
    Mina Kawai, Tomofumi Saka, Shinya Kawano, Yudai Kudo, Teiko Komori Nomura, Ryo Honda, Yuta Yoshino, Hirohito Kashiwagi, Naohito Abe, Masayoshi Oyama, Akira Ikari, Satoshi Endo.
      Resistance to androgen receptor-targeted therapies, including darolutamide (Dar), remains a major challenge in treating castration-resistant prostate cancer (CRPC). Metabolic adaptations, particularly involving dysregulated NAD+ metabolism and altered energy pathways, have been implicated in therapeutic resistance. In this study, we investigated whether Gnetin C-a resveratrol dimer derived from Gnetum gnemon-could overcome Dar resistance in prostate cancer cells. A recently established Dar-resistant 22Rv1 cell line (Dar-R) exhibited a metabolically quiescent phenotype, characterized by suppressed NAD+ metabolism, a decreased NAD+/NADH ratio, and simultaneous inhibition of both glycolysis and oxidative phosphorylation. Gnetin C demonstrated strong anticancer activity in both parental and Dar-R cells. In Dar-R cells, it downregulated NMNAT2, resulting in intracellular NAD+ depletion, and suppressed key mitochondrial proteins, leading to mitochondrial dysfunction. Gnetin C also downregulated Drp1 and upregulated Mitofusin-2, indicating a role in mitochondrial dynamics, and further inhibited glycolytic enzymes and glycolytic activity. These combined effects contributed to its potent anticancer activity by impairing both mitochondrial and glycolytic energy metabolism. Notably, Gnetin C significantly enhanced Dar sensitivity in Dar-R cells, accompanied by increased production of total and mitochondrial reactive oxygen species and the induction of apoptosis. These findings identify Gnetin C as a promising candidate for overcoming drug resistance in CRPC through metabolic disruption.
    Keywords:  Anticancer drug resistance; Darolutamide; Energy metabolism; Gnetin C; NAD(+) metabolism; Prostate cancer
    DOI:  https://doi.org/10.1016/j.bbrc.2025.152009
  8. BMC Cancer. 2025 May 19. 25(1): 895
    From genes to therapy: a lipid Metabolism-Related genetic risk model predicts HCC outcomes and enhances immunotherapy.
    Lei Xu, Ting Xiao, Tengfei Chao, Huihua Xiong, Wei Yao.
       BACKGROUND: Hepatocellular Carcinoma (HCC) is related to dysregulated lipid metabolism and immunosuppressive microenvironment. This study developed a genetic risk model using lipid metabolism-related genes to predict survival and immune patterns in HCC patients.
    METHODS: Differentially expressed genes (DEGs) related to lipid metabolism were identified in HCC via the TCGA-LIHC dataset. A risk model for survival prediction was constructed via DEGs related to survival. The immune signature associated with the risk model was also evaluated by the CIBERSORT algorithm, tumor immune dysfunction and exclusion algorithm, and single sample gene set enrichment analysis.
    RESULTS: This study identified six lipid metabolism-related genes, ADH4, LCAT, CYP2C9, CYP17A1, LPCAT1, and ACACA, to construct a lipid metabolism-related gene risk model that can divide HCC patients into low- and high-risk groups. Internal and external validation verified that the risk model could be a signature that could effectively predict HCC patient prognosis. High-risk patients showed disrupted immune cell profiles, reduced tumor-killing capacity, and increased expression of immune checkpoint genes. However, they responded more favorably to immune checkpoint inhibitor (ICB) therapy. The top ten hub genes related to the risk model were associated with tumor progression and deteriorating prognosis. In vitro experiments verified that the downregulation of the top 1 hub gene CDK1 was correlated to the HCC cell proliferation.
    CONCLUSION: The risk model constructed using lipid metabolism-related genes could effectively predict prognosis and was related to the immunosuppressive microenvironment and ICB immunotherapy. The hub genes related to the risk model were potential therapeutic targets.
    Keywords:  Bioinformatics; Hepatocellular carcinoma; Immune checkpoint Blockade; Lipid metabolism; Risk model; Survival prediction; Tumor immunity
    DOI:  https://doi.org/10.1186/s12885-025-14306-6
  9. Cancer Cell. 2025 May 12. pii: S1535-6108(25)00172-2. [Epub ahead of print]
    Isocitrate dehydrogenase 1 primes group-3 medulloblastomas for cuproptosis.
    Derek Dang, Akash Deogharkar, John McKolay, Kyle S Smith, Pooja Panwalkar, Simon Hoffman, Wentao Tian, Sunjong Ji, Ana P Azambuja, Siva Kumar Natarajan, Joanna Lum, Jill Bayliss, Katie Manzeck, Stefan R Sweha, Erin Hamanishi, Matthew Pun, Diya Patel, Sagar Rau, Olamide Animasahun, Abhinav Achreja, Martin P Ogrodzinski, Jutta Diessl, Jennifer Cotter, Debra Hawes, Fusheng Yang, Robert Doherty, Andrea T Franson, Allison R Hanaford, Charles G Eberhart, Eric H Raabe, Brent A Orr, Robert J Wechsler-Reya, Brandon Chen, Costas A Lyssiotis, Yatrik M Shah, Sophia Y Lunt, Ruma Banerjee, Alexander R Judkins, John R Prensner, Carl Koschmann, Sebastian M Waszak, Deepak Nagrath, Marcos Simoes-Costa, Paul A Northcott, Sriram Venneti.
      MYC-driven group-3 medulloblastomas (MBs) are malignant pediatric brain cancers without cures. To define actionable metabolic dependencies, we identify upregulation of dihydrolipoyl transacetylase (DLAT), the E2-subunit of pyruvate dehydrogenase complex (PDC) in a subset of group-3 MB with poor prognosis. DLAT is induced by c-MYC and targeting DLAT lowers TCA cycle metabolism and glutathione synthesis. We also note upregulation of isocitrate dehydrogenase 1 (IDH1) gene expression in group-3 MB patient tumors and suppression of IDH1 epigenetically reduces c-MYC and downstream DLAT levels in multiple c-MYC amplified cancers. DLAT is a central regulator of cuproptosis (copper-dependent cell death) induced by the copper ionophore elesclomol. DLAT expression in group-3 MB cells correlates with increased sensitivity to cuproptosis. Elesclomol is brain-penetrant and suppresses tumor growth in vivo in multiple group-3 MB animal models. Our data uncover an IDH1/c-MYC dependent vulnerability that regulates DLAT levels and can be targeted to kill group-3 MB by cuproptosis.
    Keywords:  cancer metabolism; cell death; copper; cuproptosis; elesclomol; epigenetics; pediatric brain tumor; protein lipoylation
    DOI:  https://doi.org/10.1016/j.ccell.2025.04.013
  10. Cancer Lett. 2025 May 18. pii: S0304-3835(25)00375-1. [Epub ahead of print] 217808
    Ketogenesis instigates immune suppression in enzalutamide resistant prostate cancer via OTUD7B β-hydroxybutyrylation.
    Haoran Jiang, Yuan Zeng, Weiqiang Ning, Junkai Hong, Moyang Zhu, Ping Li, Fangdie Ye, Zhifa Chen, Haoran Chen, Wei Chen, Gang Li, Hang Huang.
      Next-generation androgen receptor inhibitors are the primary treatment for metastatic prostate cancer. Unfortunately, the majority of patients rapidly develop resistance. Resistance to enzalutamide has been linked to the emergence of an immunosuppressive tumor, although the underlying mechanisms remain poorly understood. In this study, we observed a marked overexpression of enzymes involved in the ketogenic pathway in enzalutamide-induced castration-resistant prostate cancer, which contributed to immune desertification and resistance to immunotherapy. Mechanistically, upregulation of the ketogenic pathway led to the accumulation of β-hydroxybutyrate, which promoted β-hydroxybutyrylation of the cell cycle-regulated deubiquitinase OTUD7B at lysine 511. This modification impaired the degradation of APC/C substrates, resulting in a subsequent reduction in cytoplasmic double-stranded DNA accumulation, thereby attenuating cGAS-STING activation and interferon expression. These findings shed light on the metabolic adaptations and immune escape driven by androgen receptor signaling inhibitors, potentially informing the development of more effective and durable therapeutic approaches in the near future.
    DOI:  https://doi.org/10.1016/j.canlet.2025.217808
  11. Cell Biosci. 2025 May 16. 15(1): 61
    The HNRNPC/CELF2 signaling pathway drives glycolytic reprogramming and mitochondrial dysfunction in drug-resistant acute myeloid leukemia.
    Xiang Ma, Haodong Li, Ziqi Zhao, Changchun Li, Man Wang, Lele Zhang, Yutong Zhao, Haipeng Su, Feng Wang, Jiai Hua.
       BACKGROUND: Acute myeloid leukemia (AML) is an aggressive cancer with high treatment resistance, often leading to poor patient outcomes. Metabolic reprogramming plays a critical role in AML progression, influencing drug resistance (DR) and tumor survival. This study investigates the HNRNPC/CELF2 signaling pathway and its impact on AML cell metabolism and DR.
    RESULTS: The study identified that HNRNPC regulates the expression of CELF2 through m6 A modification. In drug-resistant AML cells, increased HNRNPC expression and decreased CELF2 expression were associated with upregulated glycolysis, enhanced glucose consumption, lactate production, and mitochondrial dysfunction. Knockdown of HNRNPC reduced glycolysis and cell invasion, while CELF2 knockdown reversed these effects. Conversely, HNRNPC overexpression enhanced glycolysis and cell migration, which were counteracted by CELF2 overexpression.
    CONCLUSIONS: The HNRNPC/CELF2 axis plays a pivotal role in metabolic reprogramming, driving AML progression and chemotherapy resistance. Targeting this pathway may offer new therapeutic strategies to overcome resistance and improve treatment outcomes in AML patients.
    Keywords:  Acute myeloid leukemia; CUGBP elav-like family member 2; Cell migration; Drug resistance; Glucose metabolism reprogramming; Heterogeneous nuclear ribonucleoprotein C
    DOI:  https://doi.org/10.1186/s13578-025-01386-x
  12. Gut. 2025 May 16. pii: gutjnl-2024-334630. [Epub ahead of print]
    High-protein diets alleviate tumour growth and drug resistance by promoting AKT aggregation and turnover.
    Lang Bu, Yi Zhang, Yaqing Su, Xueji Wu, Bing Gao, Lei Wang, Wei Xie, Qiwei Jiang, Jianping Guo.
       BACKGROUND: Despite the long-standing recommendations of high-protein diets for patients with cancer, the precise mechanisms of this dietary approach in benefiting tumour suppression and enhancing sensitivity to chemotherapy remain elusive.
    OBJECTIVE: To investigate the effect and underlying mechanism of high-protein diets in promoting cancer drug resistance. Characterisation of AKT regulation in this setting will provide new strategies to combat liver cancer.
    DESIGN: The role of high-protein diets in cancer drug resistance was analysed in cells and in syngeneic mouse models. In vivo and in vitro kinase and ubiquitination assays were employed to detect AKT phosphorylation and ubiquitination modifications. Clustered regularly interspaced short palindromic repeats (CRISPR)-based screen was used to identify the E3 ligase for AKT. Generation of Akt1T72E knock-in mice and Traf5 knockout mice was employed.
    RESULTS: High-protein diets repress tumour growth and sensitise tumour to chemotherapies. Specifically, S6K1 directly phosphorylates AKT, leading to acute inactivation and long-term instability of AKT protein. S6K1 promotes AKT aggregation and facilitates its interaction with TRAF5, resulting in AKT degradation in response to amino acid stimuli. Traf5 knockout mice exhibit high AKT protein levels, insulin resistance and counteracting protein diet-induced tumour repression. While a reversible phenomenon has been observed in the constitutive phosphor-mimetic Akt1T72E knock-in mice, which manifest retarded liver tumourigenesis in C-Myc transgenic mice.
    CONCLUSIONS: Our results highlight a fine-tuned regulation of AKT by S6K1-mediated phosphorylation and TRAF5-dictated ubiquitination and degradation, offering a strategy for integrating chemotherapy with high-protein diets to enhance cancer treatment efficacy.
    Keywords:  DIET; DRUG RESISTANCE; HEPATOBILIARY CANCER; MOLECULAR ONCOLOGY
    DOI:  https://doi.org/10.1136/gutjnl-2024-334630
  13. Discov Oncol. 2025 May 23. 16(1): 897
    Role of fructose in renal cell carcinoma progression.
    Jixuan Miao, Di Wang, Ruochong Pang, Hao Zhang, Yuyun Wu, Xingwei Sun, Yong Jin.
      Renal cell carcinoma (RCC) is a highly malignant tumor with a poor prognosis, underscoring the urgent need for novel therapeutic strategies. RCC cells exhibit rapid proliferation and high metabolic demands, leading to hypoglycemic and hypoxic conditions within the tumor microenvironment (TME). Our study reveals that the fructose transporter Glut5 is prominently expressed in RCC, facilitating increased fructose uptake. This compensatory mechanism supports RCC survival under glucose deprivation and hypoxia. Fructose utilization sustains RCC proliferation, migration, and colony formation in vitro, significantly reduces apoptosis, and accelerates renal cancer growth in vivo. Mechanistically, fructose activates the cAMP/PKA signaling pathway, driving metabolic reprogramming and promoting tumor progression. Furthermore, 2,5-dehydro-D-mannitol (2,5-AM), a competitive inhibitor of fructose transport, significantly inhibits RCC growth both in vivo and in vitro. These findings provide new insights into the role of fructose metabolism in RCC progression and suggest potential therapeutic targets.
    Keywords:  CAMP/PKA signaling pathway; Fructose; Renal cell carcinoma; Tumor microenvironment; Tumor progression
    DOI:  https://doi.org/10.1007/s12672-025-02688-9
  14. Drug Resist Updat. 2025 May 10. pii: S1368-7646(25)00051-2. [Epub ahead of print]81 101250
    Targeting SLC7A11 with sorafenib sensitizes stereotactic body radiotherapy in colorectal cancer liver metastasis.
    Jiashuai He, Yiran Zhang, Simin Luo, Zhan Zhao, Tianmu Mo, Hanyang Guan, Haoquan Li, Zili Bian, Xiangwei Zhang, Shenghui Qiu, Shijin Liu, Wang Tang, Bo Shi, Minfeng Chen, Dongmei Zhang, Yunlong Pan, Jinghua Pan.
      Colorectal cancer (CRC) with hepatic metastasis is associated with poor prognosis. Stereotactic body radiotherapy (SBRT) can provide local control for unresectable hepatic metastases of patients with CRC. However, the mechanisms of responsiveness to SBRT in metastatic CRC (mCRC) remain unclear. We aimed to identify a strategy to enhance the efficacy of SBRT in patients with CRC liver metastases and its mechanisms. Transcriptomic sequencing of CRC cells exposed to SBRT revealed that SBRT inhibited SLC7A11 expression. Downregulation of SLC7A11 enhanced the sensitivity of CRC cells to SBRT via ferroptosis. SBRT diminished the ability of tumor cells to sustain oxidative stress by impeding the phosphorylation of JNK and c-Jun and the transcription of NRF2. Furthermore, sorafenib, which targets SLC7A11, exerted inhibitory effects on tumor growth when used in combination with SBRT. A phase II clinical trial confirmed that sorafenib combined with SBRT overcame the resistance of liver mCRC with high SLC7A11 expression by inducing ferroptosis. The combination of SBRT and sorafenib demonstrated favorable clinical effects and safety, making it a good option for patients with CRC liver metastasis. STATEMENT OF SIGNIFICANCE: A novel strategy using the combination of SBRT and sorafenib for the treatment of patients with CRC hepatic metastasis was investigated. This strategy overcomes the radiation therapy resistance of mCRC by inhibiting SLC7A11 expression and promoting ferroptosis.
    Keywords:  Colorectal cancer; Cystine/glutamate antiporter xCT; Liver metastasis; Phase II single-arm clinical trial; SBRT; Sorafenib, Ferroptosis
    DOI:  https://doi.org/10.1016/j.drup.2025.101250
  15. Mol Med. 2025 May 21. 31(1): 199
    Metformin reverses 5-FU resistance induced by radiotherapy through mediating folate metabolism in colorectal cancer.
    Shuxuan Wang, Yanyan Lin, Qianqian Zhao, Huanliang Chen, Shisuo Du, Zhaochong Zeng.
       PURPOSE: Radiation therapy has revolutionized the treatment of primary or liver metastases in colorectal cancer (CRC). In colorectal cancer, conventional fractionation (1.8 ~ 2.0 Gy daily) is typically used for treatment. Nevertheless, there is a paucity of research investigating the potential implications of radiation therapy-induced alterations in the expression levels of regulatory genes on resistance to chemotherapy agents. Herein, we explored the mechanism by which conventional fractionation drives 5-fluorouracil (5-FU) resistance and metformin (Met) rescued 5-FU resistance in CRC.
    METHODS AND MATERIALS: RNA sequencing, differential genes expression analysis was performed to identify the 5-FU resistance genes after irradiation (according to the convention of cell irradiation, 2 Gy × 8 scheme was selected). Drug sensitivity assay, immunofluorescence staining, folate analogs concentration measurement was used to explore the biological function of histocompatibility minor 13 (HM13) and γ-Glutamyl Hydrolase (GGH). Combined chemosensitivity test and xenograft mouse model has been used to gain insights into the underlying clinical value of the combination of 5-FU and Met.
    RESULTS: The conventional fractionation scheme (2 Gy × 8) induced resistance to 5-FU in the CRC cell line HCT-15, accompanied by an elevated RNA expression level of peptidase HM13. Mechanistically, the increased expression of HM13 caused an abnormal shearing of the N-terminal signal peptide of γ-Glutamyl Hydrolase (GGH), which resulted in decreased intracellular content of 5, 10-methylenetetrahydrofolate (5,10-CH2-THF).
    CONCLUSION: We revealed a new mechanism of 5-FU resistance induced by irradiated with 2 Gy × 8 through the HM13-GGH-5,10-CH2-THF axis. The synergistic effect of Met and 5-FU can rescue 5-FU resistance after conventional fractionated irradiation. In summary, this work will help to reveal the mechanisms of IR-induced 5-FU resistance, which is important for finding new therapeutic targets and improving the efficacy of chemotherapy regimens after radiotherapy.
    Keywords:  5-FU; Folate metabolism; Histocompatibility minor 13; Irradiation; Metformin
    DOI:  https://doi.org/10.1186/s10020-025-01206-5
  16. Cancer Res. 2025 May 20.
    Recharacterization of the Tumor Suppressive Mechanism of RSL3 Identifies the Selenoproteome as a Druggable Pathway in Colorectal Cancer.
    Stephen L DeAngelo, Liang Zhao, Sofia Dziechciarz, Myungsun Shin, Sumeet Solanki, Andrii Balia, Marwa O El-Derany, Cristina Castillo, Yao Qin, Nupur K Das, Hannah N Bell, Joao A Paulo, Yuezhong Zhang, Nicholas J Rossiter, Elizabeth C McCulla, Jianping He, Indrani Talukder, Billy Wai-Lung Ng, Zachary T Schafer, Nouri Neamati, Joseph D Mancias, Markos Koutmos, Yatrik M Shah.
      Ferroptosis is a non-apoptotic form of cell death driven by iron-dependent lipid peroxide accumulation. Colorectal cancer (CRC) cells feature elevated intracellular iron and reactive oxygen species (ROS) that heighten ferroptosis sensitivity. The ferroptosis inducer (S)-RSL3 ([1S,3R]-RSL3) is widely described as a selective inhibitor of the selenocysteine-containing enzyme (selenoprotein) glutathione peroxidase 4 (GPX4), which detoxifies lipid peroxides utilizing glutathione. However, through chemical controls utilizing the (R) stereoisomer of RSL3 ([1R,3R]-RSL3) that does not bind GPX4, combined with inducible genetic knockdowns of GPX4 in CRC cell lines, we revealed here that GPX4 dependency does not always align with (S)-RSL3 sensitivity, questioning the current characterization of GPX4 as the primary target of (S)-RSL3. Affinity pull-down mass spectrometry with modified (S)-RSL3 probes identified multiple selenoprotein targets, indicating broad selenoprotein inhibition. Further investigation of the therapeutic potential of broadly disrupting the selenoproteome as a therapeutic strategy in CRC showed that the selenoprotein inhibitor auranofin, an FDA-approved gold-salt, chemically induced oxidative cell death and ferroptosis in CRC models in vitro and in vivo. Similarly, genetic perturbation of ALKBH8, a tRNA-selenocysteine methyltransferase required for selenoprotein translation, suppressed CRC growth. In summary, these findings recharacterize the mechanism of (S)-RSL3 beyond GPX4 inhibition and establish selenoproteome disruption as a CRC therapeutic strategy.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-24-3478
  17. Mol Cell Biochem. 2025 May 23.
    CD44 and SLC1A2 are commonly regulated but do not form a fusion transcript in ER+ breast cancer.
    Francesca Bonechi, Marina Bacci, Nicla Lorito, Alfredo Smiriglia, Edoardo Pagliantini, Matteo Benelli, Icro Meattini, Andrea Morandi.
      Endocrine therapy (ET) is essential for managing ER+ HER2- breast cancer; however, resistance remains a significant clinical challenge. This study investigated whether CD44-SLC1A2 gene fusions, reported in gastrointestinal malignancies, contribute to ET resistance mechanisms in breast cancer. Although no CD44-SLC1A2 fusions were detected, high expression of CD44 and SLC1A2 was associated with poor survival outcomes and identified a therapy-resistant subpopulation sustained by aspartate and glutamate metabolism, highlighting potential metabolic vulnerabilities for future therapeutic intervention.
    Keywords:  Breast cancer; Endocrine therapy; Metabolic reprogramming
    DOI:  https://doi.org/10.1007/s11010-025-05308-w
  18. Cancer Med. 2025 May;14(10): e70959
    FUT8 Is a Critical Driver of Prostate Tumour Growth and Can Be Targeted Using Fucosylation Inhibitors.
    Kayla Bastian, Margarita Orozco-Moreno, Huw Thomas, Kirsty Hodgson, Eline A Visser, Emiel Rossing, Johan F A Pijnenborg, Nienke Eerden, Laura Wilson, Hasvini Saravannan, Oliver Hanley, Grace Grimsley, Fiona Frame, Ziqian Peng, Bridget Knight, Paul McCullagh, John McGrath, Malcolm Crundwell, Lorna Harries, Norman J Maitland, Rakesh Heer, Ning Wang, Ethan D Goddard-Borger, Ramon Hurtado Guerrero, Thomas J Boltje, Richard R Drake, Emma Scott, David J Elliott, Jennifer Munkley.
       BACKGROUND: An unmet clinical need requires the discovery of new treatments for men facing advanced prostate cancer. Aberrant glycosylation is a universal feature of cancer cells and plays a key role in tumour growth, immune evasion and metastasis. Alterations in tumour glycosylation are closely associated with prostate cancer progression, making glycans promising therapeutic targets. Fucosyltransferase 8 (FUT8) drives core fucosylation by adding α1,6-fucose to the innermost GlcNAc residue on N-glycans. While FUT8 is recognised as a crucial factor in cancer progression, its role in prostate cancer remains poorly understood.
    METHODS & RESULTS: Here, we demonstrate using multiple independent clinical cohorts that FUT8 is upregulated in high grade and metastatic prostate tumours, and in the blood of prostate cancer patients with aggressive disease. Using novel tools, including PhosL lectin immunofluorescence and N-glycan MALDI mass spectrometry imaging (MALDI-MSI), we find FUT8 underpins the biosynthesis of malignant core fucosylated N-glycans in prostate cancer cells and using both in vitro and in vivo models, we find FUT8 promotes prostate tumour growth, cell motility and invasion. Mechanistically we show FUT8 regulates the expression of genes and signalling pathways linked to prostate cancer progression. Furthermore, we find that fucosylation inhibitors can inhibit the activity of FUT8 in prostate cancer to suppress the growth of prostate tumours.
    CONCLUSIONS: Our study cements FUT8-mediated core fucosylation as an important driver of prostate cancer progression and suggests targeting FUT8 activity for prostate cancer therapy as an exciting area to explore.
    Keywords:  core fucosylation; fucosylation inhibitors; fucosyltransferase 8 (FUT8); glycans; prostate cancer; therapeutics; tumour growth
    DOI:  https://doi.org/10.1002/cam4.70959
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