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Review
. 2020 Oct 7:10:578418.
doi: 10.3389/fonc.2020.578418. eCollection 2020.

The Double-Edge Sword of Autophagy in Cancer: From Tumor Suppression to Pro-tumor Activity

Rodolfo Chavez-Dominguez  1   2 , Mario Perez-Medina  1   3 , Jose S Lopez-Gonzalez  1 , Miriam Galicia-Velasco  1 , Dolores Aguilar-Cazares  1
Affiliations
Review

The Double-Edge Sword of Autophagy in Cancer: From Tumor Suppression to Pro-tumor Activity

Rodolfo Chavez-Dominguez et al. Front Oncol. .

Abstract

During tumorigenesis, cancer cells are exposed to a wide variety of intrinsic and extrinsic stresses that challenge homeostasis and growth. Cancer cells display activation of distinct mechanisms for adaptation and growth even in the presence of stress. Autophagy is a catabolic mechanism that aides in the degradation of damaged intracellular material and metabolite recycling. This activity helps meet metabolic needs during nutrient deprivation, genotoxic stress, growth factor withdrawal and hypoxia. However, autophagy plays a paradoxical role in tumorigenesis, depending on the stage of tumor development. Early in tumorigenesis, autophagy is a tumor suppressor via degradation of potentially oncogenic molecules. However, in advanced stages, autophagy promotes the survival of tumor cells by ameliorating stress in the microenvironment. These roles of autophagy are intricate due to their interconnection with other distinct cellular pathways. In this review, we present a broad view of the participation of autophagy in distinct phases of tumor development. Moreover, autophagy participation in important cellular processes such as cell death, metabolic reprogramming, metastasis, immune evasion and treatment resistance that all contribute to tumor development, is reviewed. Finally, the contribution of the hypoxic and nutrient deficient tumor microenvironment in regulation of autophagy and these hallmarks for the development of more aggressive tumors is discussed.

Keywords: autophagy; carcinogenesis; cell death; chemotherapy and _targeted therapy resistance; immune evasion; metabolic reprograming; metastasis; tumor microenvironment.

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Figures

Figure 1
Figure 1
Regulation of the mammalian autophagy. Under low nutrient conditions or starvation, the energy sensor AMPK detects alterations in energy pools (AMP/ATP ratio) inhibiting autophagy repressor mTOR and activating ULK1/2 complex. For phagophore formation, ULK1/2 complex activates the Beclin-1 P13K-class III complex. Additional systems activate (red arrows) or inhibit (blue arrows) the activity and assembly of the complex. The elongation of the isolation membrane requires the participation of two ubiquitin-like conjugation systems. The formation of the Atg12-Atg5-Atg16 complex involves the activity of Atg7 and Atg10. The LC3 requires the participation of Atg4 to hydrolyze LC3 into LC3-I, Atg3 as well as Atg7 for conjugation of LC3-II to pohosphatidyletanolamine (PE). Phagophore closure is regulated by members of ESCRT, CHMP2A VPS4. In the late steps of maturation and fusion, Dynein participates in the mobilization of auto phagosomes. The fusion of auto phagosomes with lysosomes is mediated by members of the SNARE family. Created by BioRender.com.
Figure 2
Figure 2
Crosstalk of autophagy and apoptosis in cancer. Potential carcinogenic agents induce distinct types of stress in cell, triggering autophagy or apoptosis. Under certain threshold of damage, stress-responsive transcription factors such as p53 or FOXO promote the upregulation of genes involved in control and activation of autophagy, thereby neutralizing the damage. However, if the carcinogenic stimulus persists and damage is above threshold, autophagic proteins interact with pro- or anti- apoptotic molecules triggering intrinsic or extrinsic apoptosis, therefore limiting the growth of incipient tumor cells. Created by BioRender.com.
Figure 3
Figure 3
Metabolic stress and autophagy. During the oncogenic process, the proliferation rate and the microenvironmental conditions promote that the tumor cells reprogram their metabolism. Consequently, autophagy plays an essential role in this reprogramming, providing different substrates to feed the pathways of tumor cells. However, the induction of autophagy depends on the stimuli to which the cell is subjected, the alteration of oncogenes such as MYC or RAS, the autophagy process is inhibited and during some microenvironmental tumor conditions such as hypoxia, autophagy is promoted. Created by BioRender.com.
Figure 4
Figure 4
Uncontrolled cell proliferation produces a high demand for oxygen and nutrients. As a result, the tumor becomes hypoxic and starved. These metabolic changes generate the activation of the epithelium-mesenchymal transition (EMT) program and the presence in the environment of factors that promotes metastasis and autophagy such as TGF-β. Autophagy participates in two ways favoring cellular migration: (a) avoiding anoikis and (b) in the turnover of the focal adhesion. Created by BioRender.com.
Figure 5
Figure 5
Autophagy as an immune evasion mechanism. Autophagy induced by environmental stress such as hypoxia promotes the escape to CTL or NK mediated elimination of tumors cells. (A) Hypoxia, by an undefined mechanism, releases pSTAT3 from p62, thereby degrading p62 by autophagy and favoring pSTAT3 nuclear localization to up-regulate transcription of antiapoptotic genes. (B) During hypoxia, tumor cells activate autophagy to sequester and degrade cytotoxic granules released by NK cells or CTLs, thus impeding the elimination of tumor cells. (C) Selective ER phagy might participate in degradation of MHC-l molecules during their biogenesis. NBR1 associate to MHC-l molecules or their chaperones in ER. Decreased surface expression of MHC-l molecules leads to impaired recognition by innate or adaptive immune cells, leading to escape for immune-mediated elimination. Created by BioRender.com.
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