ABSTRACT

Radiotherapy is one of the curative mainstays of prostate cancer; however, its efficacy is often diminished by tumor radioresistance. Depending on the stage of disease, tumors can relapse in approximately 50% of patients with prostate cancer after radiotherapy. Nevertheless, the mechanisms that drive tumor cell survival are not fully characterized, and reliable molecular prognostic markers of prostate cancer radioresistance are missing. Similar to other tumor entities, prostate cancer cells are heterogeneous in their capability to maintain tumor growth. The populations of cancer stem cells (CSCs) with self-renewal and differentiation properties are responsible for tumor development and recurrence after treatment. Eradication of these CSC populations is of utmost importance for efficient tumor cure. In a recently published study, we showed that prostate cancer cells could be radiosensitized by glutamine deprivation, resulting in DNA damage, oxidative stress, epigenetic modifications, and depletion of CSCs. Conversely, prostate cancer cells with resistance to glutamine depletion show an activation of ATG-mediated macroautophagy/autophagy as a survival strategy to withstand radiation-induced damage. Thus, a combination of targeting glutamine metabolism and autophagy blockade lead to more efficient prostate cancer radiosensitization.

Abbreviations: ATG5: autophagy related 5; CSCs: cancer stem cells; GLS: glutaminase; TCA cycle: tricarboxylic acid cycle

摘要

放疗是前列腺癌的主要治疗手段之一；然而，它的功效常常因肿瘤的放射抗性而减弱。根据疾病的阶段，大约 50% 的前列腺癌患者在放疗后会复发。然而，驱动肿瘤细胞存活的机制尚未完全表征，并且缺少可靠的前列腺癌放射抗性分子预后标志物。与其他肿瘤实体类似，前列腺癌细胞维持肿瘤生长的能力是异质的。具有自我更新和分化特性的癌症干细胞 (CSC) 群体负责治疗后肿瘤的发展和复发。根除这些 CSC 群体对于有效治愈肿瘤至关重要。在最近发表的一项研究中，我们发现前列腺癌细胞可能因缺乏谷氨酰胺而受到放射增敏，导致 DNA 损伤、氧化应激、表观遗传修饰和 CSC 耗竭。相反，对谷氨酰胺耗竭有抵抗力的前列腺癌细胞表现出激活 ATG 介导的巨自噬/自噬作为抵御辐射诱导损伤的生存策略。因此，靶向谷氨酰胺代谢和自噬阻断的组合导致更有效的前列腺癌放射增敏。对谷氨酰胺耗竭有抵抗力的前列腺癌细胞显示出 ATG 介导的巨自噬/自噬的激活，作为抵御辐射诱导损伤的生存策略。因此，靶向谷氨酰胺代谢和自噬阻断的组合导致更有效的前列腺癌放射增敏。对谷氨酰胺耗竭有抵抗力的前列腺癌细胞显示出 ATG 介导的巨自噬/自噬的激活，作为抵御辐射诱导损伤的生存策略。因此，靶向谷氨酰胺代谢和自噬阻断的组合导致更有效的前列腺癌放射增敏。

缩写： ATG5：自噬相关5；CSCs：癌症干细胞；GLS：谷氨酰胺酶；TCA循环：三羧酸循环