ATM deficiency promotes progression of CRPC by enhancing Warburg effect
| العنوان: | ATM deficiency promotes progression of CRPC by enhancing Warburg effect |
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| المؤلفون: | Tao Zeng, Jeff Groth, Ruya Zhao, Xufeng Chen, Yulei Tao, Hailiang Hu, Jiaoti Huang, Enze Ma, Lingfan Xu, Chaozhao Liang |
| المصدر: | Endocrine-Related Cancer. 26:59-71 |
| بيانات النشر: | Bioscientifica, 2019. |
| سنة النشر: | 2019 |
| مصطلحات موضوعية: | Male, 0301 basic medicine, Mitochondrial ROS, Cancer Research, DNA repair, Endocrinology, Diabetes and Metabolism, Poly ADP ribose polymerase, Ataxia Telangiectasia Mutated Proteins, Synthetic lethality, Naphthalenes, urologic and male genital diseases, Article, Mice, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, Cell Line, Tumor, Animals, Humans, Lactic Acid, Cell Proliferation, L-Lactate Dehydrogenase, Chemistry, Cell growth, Warburg effect, Prostatic Neoplasms, Castration-Resistant, Glucose, 030104 developmental biology, Oncology, Anaerobic glycolysis, 030220 oncology & carcinogenesis, PARP inhibitor, Disease Progression, Cancer research |
| الوصف: | ATM is a well-known master regulator of double strand break (DSB) DNA repair and the defective DNA repair has been therapeutically exploited to develop PARP inhibitors based on the synthetic lethality strategy. ATM mutation is found with increased prevalence in advanced metastatic castration-resistant prostate cancer (mCRPC). However, the molecular mechanisms underlying ATM mutation-driving disease progression are still largely unknown. Here, we report that ATM mutation contributes to the CRPC progression through a metabolic rather than DNA repair mechanism. We showed that ATM deficiency generated by CRISPR/Cas9 editing promoted CRPC cell proliferation and xenograft tumor growth. ATM deficiency altered cellular metabolism and enhanced Warburg effect in CRPC cells. We demonstrated that ATM deficiency shunted the glucose flux to aerobic glycolysis by upregulating LDHA expression, which generated more lactate and produced less mitochondrial ROS to promote CRPC cell growth. Inhibition of LDHA by siRNA or inhibitor FX11 generated less lactate and accumulated more ROS in ATM-deficient CRPC cells and therefore potentiated the cell death of ATM-deficient CRPC cells. These findings suggest a new therapeutic strategy for ATM-mutant CRPC patients by targeting LDHA-mediated glycolysis metabolism, which might be effective for the PARP inhibitor resistant mCRPC tumors. |
| تدمد: | 1479-6821 1351-0088 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::7086abd2263f975628e634ac7756c20bTest https://doi.org/10.1530/erc-18-0196Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....7086abd2263f975628e634ac7756c20b |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 14796821 13510088 |
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