Sirtuins' control of autophagy and mitophagy in cancer

https://doi.org/10.1016/j.pharmthera.2020.107748Get rights and content

Abstract

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.

Introduction

Cellular transformation leading to cancer promotion as well as cancer progression and metastasis are the results not only of mutations but also of many other molecular changes whose importance has been recognized by including them among the hallmarks of cancer (Hanahan and Weinberg, 2011). Although each cancer has its own history that renders it unique being the reason why this pathology is so difficult to eradicate, there are some common aspects among tumors that may deserve more attention and better understanding because they may reveal useful new lines of intervention. Among new and emerging hallmarks of cancer, autophagy, mitophagy and metabolic reprogramming deserve particular attention and are at the center of a large number of studies, projects and clinical trials. In fact, autophagy, a self-eating mechanism exploited by cells for recycling or dispose of either damaged proteins or organelles, has important implication for cellular survival in conditions of stress such as starvation, reactive oxygen species (ROS) induced conditions, hypoxia, etc., (Feng et al., 2020; Kawabata and Yoshimori, 2020) as well as for physiological changes such as differentiation or specialization (Iovino et al., 2012; Yang et al., 2020). Moreover, specific disposal of dysfunctional mitochondria by autophagy called mitophagy has surged as a crucial mechanism in physiological and pathological conditions (Gottlieb and Carreira, 2010). For example, mitophagy serves muscle and adipose cells during differentiation as well as during hypoxia adaptation (Gottlieb and Carreira, 2010). Interestingly, cancer cells belonging to different type of tumors highjack autophagy and mitophagy machinery to survive exogenous stresses and to thrive in extreme situations (Daskalakis et al., 2020; Wang et al., 2020b). The problem arises when observing that both an increase or decrease of autophagy and mitophagy can contribute to cancer development and that modulation of autophagy and mitophagy can change during cancer development in order to better serve cancer cells purposes (Santana-Codina et al., 2017). Recently, in cancer cells a connection between autophagy, mitophagy and metabolism has been observed. In fact, metabolic reprogramming in cancer not only provides building blocks such as lipids, nucleotides, amino acids, etc. for sustaining the growth of cancer cells but also byproducts that are used by cancer cells to increase autophagy and mitophagy (Zhang et al., 2020b). This is the case of lactate and protons (H+) obtained from oxidative glycolysis that are used for acidifying tumor microenvironment and that can induce autophagy in surrounding cells (Rabiee et al., 2019) or ammonia that is obtained from glutamine metabolism and, once released into the tumor microenvironment can induce autophagy and mitophagy in a autocrine and paracrine fashion (Eng and Abraham, 2010). On the other hand, sirtuins are a family of seven (SIRT1-7) NAD+-dependent deacylases used by mammalian cells to fine tuning their molecular response to microenvironmental changes such as nutrients availability, oxidative stress, hypoxia, inflammation, etc. (Kupis et al., 2016). In particular, sirtuins reach their goal of cellular response control in at least two ways: i) different intracellular localization with SIRT1, 6 and 7 residing in the nucleus, SIRT1 and 2 in the cytosol and SIRT3, 4 and 5 in the mitochondria, ii) multiple post translational modifications such as deacetylation, deglutarylation, desuccinylation, ADP-ribosylation, etc., of histones and transcription factors in the nucleus and metabolic enzymes or adaptors in the cytosol and mitochondria. Interestingly, many of the transcription factors, enzymes, structural proteins, etc., that are modified by sirtuins belong to metabolic pathways or to intracellular mechanisms such as autophagy and mitophagy (Lee et al., 2013; Ye et al., 2017a). For example sirtuins control glucose, lipid and amino acid metabolism in physiological and pathological conditions by regulating transcription factors and enzymes such as HIF-1α, PGC-1α, FoxO1, GDH, PEPCK-C, PPARγ, CPS1, ATGL1, c-MYC, etc. (Ye et al., 2017a). Moreover, sirtuins can directly influence autophagy by interaction and/or post-translational modification of autophagy proteins such as ATG5, ATG7 and ATG8 (Lee et al., 2008) or can indirectly increase the expression of autophagy and mitophagy proteins such as mTORC1, PARK1, Beclin-1, BNIP3, etc. (Di Sante et al., 2015; Mu et al., 2019; Qiu et al., 2016). It is becoming therefore clear that sirtuins connect and modulate metabolism with autophagy and mitophagy that, in the case of cancer, represents an important discovery because provides a tool that can be used to push cancer cells away from their pathologic equilibrium making them susceptible to new or conventional cancer therapies. In the present review we not only discuss the current knowledge of how sirtuins can control autophagy and mitophagy in cancer cells but also in the context of tumor progression and metastasis because, they represent the major challenge for oncologists. Finally, we also discuss how every single sirtuin can be involved in the control of autophagy and mitophagy by regulating cancer cell metabolism by using glutamine metabolism as an example.

Section snippets

Sirtuins: characteristics and major functions

The discovery of Sirtuin family of proteins has represented an important step for deepening our understanding of different physiological processes like control of cell proliferation, stress resistance and aging but also for the study of several diseases and different pathological conditions related to metabolism, cancer, neurodegeneration, inflammation, oxidative stress etc. (Kupis et al., 2016; Yamamoto et al., 2007). In fact, Sirtuins are evolutionary conserved from yeast to human with a high

Autophagy

Autophagy is a highly preserved catabolic pathway involved in the degradation and recycling of intracellular components. Autophagy can be defined by a selective or non-selective mechanism (Dikic and Elazar, 2018). Non-selective autophagy is characterized by a random engulfment of cytoplasm into a double membrane vesicle for the delivering to a lysosome for degradation. This process continuously takes place at low levels inside cells and helps to turn cytoplasmic constituents and recycle them to

Conclusions and questions

What is emerging by the increasing number of studies on sirtuins in cancer is that they sit and control crucial nodes of this pathology to a point that the line between cancer suppression or cancer promotion by sirtuins is very subtle and should be discussed case by case. Another important emerging aspect is that sirtuins can definitively control autophagy and mitophagy in cancer by impinging on transcription factors or proteins belonging to the autophagy and mitophagy machinery. However,

Declaration of Competing Interest

“The authors declare that there are no conflicts of interest.”

Acknowledgments

This work was supported by the Bando di Ateneo 2019 to Marco Tafani from Sapienza University, Rome, Italy.

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