Radiotherapy is one of the curative treatment options for localized prostate cancer (PCa). The curative potential of radiotherapy is mediated by irradiation-induced oxidative stress and DNA damage in tumor cells. However, PCa radiocurability can be impeded by tumor resistance mechanisms and normal tissue toxicity. Metabolic reprogramming is one of the major hallmarks of tumor progression and therapy resistance. Here, we found that radioresistant PCa cells and prostate cancer stem cells (CSCs) have a high glutamine demand. Glutaminase (GLS)-driven catabolism of glutamine serves not only for energy production but also for the maintenance of the redox state. Consequently, glutamine depletion or inhibition of critical regulators of glutamine utilization, such as glutaminase (GLS) and the transcription factor MYC results in PCa radiosensitization. On the contrary, we found that a combination of glutamine metabolism inhibitors with irradiation does not cause toxic effects on nonmalignant prostate cells. Glutamine catabolism contributes to the maintenance of CSCs through regulation of the alpha-ketoglutarate (α-KG)-dependent chromatin-modifying dioxygenase. The lack of glutamine results in the inhibition of CSCs with a high aldehyde dehydrogenase (ALDH) activity, decreases the frequency of the CSC populations in vivo and reduces tumor formation in xenograft mouse models. Moreover, this study shows that activation of the ATG5-mediated autophagy in response to a lack of glutamine is a tumor survival strategy to withstand radiation-mediated cell damage. In combination with autophagy inhibition, the blockade of glutamine metabolism might be a promising strategy for PCa radiosensitization. High blood levels of glutamine in PCa patients significantly correlate with a shorter prostate-specific antigen (PSA) doubling time. Furthermore, high expression of critical regulators of glutamine metabolism, GLS1 and MYC, is significantly associated with a decreased progression-free survival in PCa patients treated with radiotherapy. Our findings demonstrate that GLS-driven glutaminolysis is a prognostic biomarker and therapeutic target for PCa radiosensitization.

中文翻译：

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GLS驱动的谷氨酰胺分解代谢通过调节氧化还原状态，茎干和ATG5介导的自噬而有助于前列腺癌的放射敏感性

放射疗法是局限性前列腺癌（PCa）的治疗选择之一。放射疗法的治愈潜力是由辐射诱导的肿瘤细胞中的氧化应激和DNA损伤介导的。但是，肿瘤抵抗机制和正常组织毒性会阻碍PCa的放射固化能力。代谢重编程是肿瘤进展和治疗抗性的主要标志之一。在这里，我们发现抗辐射的PCa细胞和前列腺癌干细胞（CSC）对谷氨酰胺的需求很高。谷氨酰胺酶（GLS）驱动的谷氨酰胺分解代谢不仅用于产生能量，而且还用于维持氧化还原状态。因此，谷氨酰胺的消耗或谷氨酰胺利用的关键调节剂（如谷氨酰胺酶（GLS）和转录因子MYC）的抑制导致PCa放射增敏。相反，我们发现谷氨酰胺代谢抑制剂与辐射的组合不会对非恶性前列腺细胞产生毒性作用。谷氨酰胺分解代谢通过调节依赖α-酮戊二酸（α-KG）的染色质修饰双加氧酶来促进CSC的维持。缺乏谷氨酰胺会导致具有高醛脱氢酶（ALDH）活性的CSC受到抑制，降低了体内CSC群体的频率并减少了异种移植小鼠模型中的肿瘤形成。此外，这项研究表明，响应谷氨酰胺缺乏而激活ATG5介导的自噬是一种能够抵抗辐射介导的细胞损伤的肿瘤生存策略。与自噬抑制相结合，谷氨酰胺代谢的阻断可能是PCa放射增敏的有前途的策略。PCa患者的高谷氨酰胺水平与较短的前列腺特异性抗原（PSA）加倍时间显着相关。此外，在接受放射治疗的PCa患者中，谷氨酰胺代谢关键调节因子GLS1和MYC的高表达与无进展生存期降低显着相关。我们的研究结果表明，GLS驱动的谷氨酰胺分解是PCa放射增敏的预后生物标志物和治疗靶标。