Aventaggiato Michele, Vernucci Enza, Barreca Federica, Russo Matteo A, Tafani Marco
Department of Experimental Medicine, Sapienza University, Viale Regina Elena 324, 00161 Rome, Italy.
Department of Internistic, Anesthesiologic and Cardiovascular Clinical Sciences, Italy; MEBIC Consortium, San Raffaele Open University, Via val Cannuta 247, 00166 Rome, Italy.
Pharmacol Ther. 2021 May;221:107748. doi: 10.1016/j.pharmthera.2020.107748. Epub 2020 Nov 24.
Mammalian cells use a specialized and complex machinery for the removal of altered proteins or dysfunctional organelles. Such machinery is part of a mechanism called autophagy. Moreover, when autophagy is specifically employed for the removal of dysfunctional mitochondria, it is called mitophagy. Autophagy and mitophagy have important physiological implications and roles associated with cellular differentiation, resistance to stresses such as starvation, metabolic control and adaptation to the changing microenvironment. Unfortunately, transformed cancer cells often exploit autophagy and mitophagy for sustaining their metabolic reprogramming and growth to a point that autophagy and mitophagy are recognized as promising targets for ongoing and future antitumoral therapies. Sirtuins are NAD+ dependent deacylases with a fundamental role in sensing and modulating cellular response to external stresses such as nutrients availability and therefore involved in aging, oxidative stress control, inflammation, differentiation and cancer. It is clear, therefore, that autophagy, mitophagy and sirtuins share many common aspects to a point that, recently, sirtuins have been linked to the control of autophagy and mitophagy. In the context of cancer, such a control is obtained by modulating transcription of autophagy and mitophagy genes, by post translational modification of proteins belonging to the autophagy and mitophagy machinery, by controlling ROS production or major metabolic pathways such as Krebs cycle or glutamine metabolism. The present review details current knowledge on the role of sirtuins, autophagy and mitophagy in cancer to then proceed to discuss how sirtuins can control autophagy and mitophagy in cancer cells. Finally, we discuss sirtuins role in the context of tumor progression and metastasis indicating glutamine metabolism as an example of how a concerted activation and/or inhibition of sirtuins in cancer cells can control autophagy and mitophagy by impinging on the metabolism of this fundamental amino acid.
哺乳动物细胞利用一套专门且复杂的机制来清除发生改变的蛋白质或功能失调的细胞器。这种机制是一种名为自噬的机制的一部分。此外，当自噬专门用于清除功能失调的线粒体时，它被称为线粒体自噬。自噬和线粒体自噬具有重要的生理意义，与细胞分化、对饥饿等应激的抵抗、代谢控制以及对不断变化的微环境的适应相关。不幸的是，转化的癌细胞常常利用自噬和线粒体自噬来维持其代谢重编程和生长，以至于自噬和线粒体自噬被认为是当前及未来抗肿瘤治疗的有前景的靶点。沉默调节蛋白是依赖烟酰胺腺嘌呤二核苷酸（NAD+）的去酰基酶，在感知和调节细胞对诸如营养物质可用性等外部应激的反应中起基本作用，因此参与衰老、氧化应激控制、炎症、分化和癌症。所以很明显，自噬、线粒体自噬和沉默调节蛋白有许多共同之处，以至于最近沉默调节蛋白已与自噬和线粒体自噬的调控联系起来。在癌症背景下，这种调控是通过调节自噬和线粒体自噬基因的转录、对属于自噬和线粒体自噬机制的蛋白质进行翻译后修饰、控制活性氧（ROS）产生或诸如三羧酸循环或谷氨酰胺代谢等主要代谢途径来实现的。本综述详细阐述了目前关于沉默调节蛋白、自噬和线粒体自噬在癌症中的作用的知识，然后继续讨论沉默调节蛋白如何在癌细胞中控制自噬和线粒体自噬。最后，我们讨论沉默调节蛋白在肿瘤进展和转移背景下的作用，以谷氨酰胺代谢为例，说明癌细胞中沉默调节蛋白的协同激活和/或抑制如何通过影响这种基本氨基酸的代谢来控制自噬和线粒体自噬。
