Autophagy in tumorigenesis and energy metabolism: friend by day, foe by night

Abstract

Autophagy is the mechanism by which cells consume parts of themselves to survive starvation and stress. This self-cannibalization limits cell death and tissue inflammation, recycles energy and biosynthetic substrates and removes damaged proteins and organelles, accumulation of which is toxic. In normal tissues, autophagy-mediated damage mitigation may suppress tumorigenesis, while in advanced tumors macromolecular recycling may support survival by buffering metabolic demand under stress. As a result, autophagy-activation in normal cells may suppress tumorigenesis, while autophagy inhibition may be beneficial for the therapy of established tumors. The mechanisms by which autophagy supports cancer cell metabolism are slowly emerging. As cancer is being increasingly recognized as a metabolic disease, how autophagy-mediated catabolism impacts cellular and mammalian metabolism and tumor growth is of great interest. Most cancer therapeutics induce autophagy, either directly by modulating signaling pathways that control autophagy in the case of many targeted therapies, or indirectly in the case of cytotoxic therapy. However, the functional consequence of autophagy induction in the context of cancer therapy is not yet clear. A better understanding of how autophagy modulates cell metabolism under various cellular stresses and the consequences of this on tumorigenesis will help develop better therapeutic strategies against cancer prevention and treatment.

Figure 1. Regulation of autophagy under nutrient deprivation and its interaction with central carbon metabolism

The major extra-cellular nutrient sensing pathways, controlled by PI3K-I and adenosine monophosphate activated kinase (AMPK) tightly regulate autophagy through mTOR signaling, although other mTOR independent mechanisms exist [–11]. Under nutrient-replete conditions, autophagy is inhibited by mTOR and inactivation of the ULK1 complex. Metabolic stress relieves this inhibition to activate autophagy, and activates AMPK. AMPK inhibits mTOR by activating its negative regulator, the tuberous sclerosis protein 2 (TSC2) and inhibiting its positive-regulatory subunit, Raptor. The ULK1 complex activates the vacuolar sorting protein 34 (hVPS34)- and Beclin1-containing complexes (complex I and complex II), to initiate phagophore formation (Figure 1) [9]. Phagophores nucleate and expand around the cargo encapsulating it and targeting it to lysosomes for degradation. Degradation products of autophagy substrates may re-enter glycolysis and the TCA cycle for anabolic as well as catabolic processes leading to generation of energy and biomass production. For an extensive review of other forms of autophagy regulation, please see [11,12,55].

Figure 2. Mechanism of autophagy-mediated stress survival and tumor cell dormancy

Metabolic stress is a potent trigger for senescence or apoptosis as two important tumor suppression mechanisms. Autophagy is induced under metabolic stress as a survival mechanism that delays apoptosis [29,56]. Apoptosis-defective cells survive metabolic stress through autophagy-mediated stress-adaptation. Upon prolonged stress, cells exit the cell cycle, and alter gene expression and metabolism to conserve energy leading to senescence, dormancy or quiescence [29,31]. Upon removal of stress, dormant cells re-enter the cell cycle and resume proliferation that can potentially lead to regeneration and tumor relapse. Deciphering the molecular mechanisms of this stress-adaptation is important to prevent tumor dormancy to improve cancer therapy.

Figure 3. Mechanisms by which autophagy defects promote tumorigenesis

Metabolic stress due to hypoxia, nutrient deprivation and oncogene activation trigger proliferation but also induce apoptosis, which limits tumor growth. Metabolic stress activates autophagy as a protective mechanism in metabolically stressed tumor regions. Autophagy-competent cells survive, while autophagy-defective cells succumb to cell death in hypoxic regions, promoting a chronic inflammatory state that can favor tumor growth [3,29,31]. Thus by limiting tissue damage, autophagy may suppress tumorigenesis. At the subcellular level, metabolic stress also induces oxidative damage and p62-accumulation. In normal cells, coordinate induction of autophagy degrades damaged proteins, lipids and organelles, preventing toxic buildup of “cellular garbage” in a p62-dependent manner, thus protecting the genome. In autophagy-defective cells, the degradation of toxic material is prevented, leading to persistently high levels of p62 and the formation of p62-containing protein aggregates, accumulation of damaged mitochondria and ROS production, leading to DNA damage and chromosomal instability that can promote tumorigenesis [3,32].