A perspective on the role of autophagy in cancer

Abstract

Autophagy refers to a ubiquitous set of catabolic pathways required to achieve proper cellular homeostasis. Aberrant autophagy has been implicated in a multitude of diseases including cancer. In this review, we highlight pioneering and groundbreaking research that centers on delineating the role of autophagy in cancer initiation, proliferation and metastasis. First, we discuss the autophagy-related (ATG) proteins and their respective roles in the de novo formation of autophagosomes and the subsequent delivery of cargo to the lysosome for recycling. Next, we touch upon the history of cancer research that centers upon ATG proteins and regulatory mechanisms that control an appropriate autophagic response and how these are altered in the diseased state. Then, we discuss the various discoveries that led to the idea of autophagy as a double-edged sword when it comes to cancer therapy. This review also briefly narrates how different types of autophagy-selective macroautophagy and chaperone-mediated autophagy, have been linked to different cancers. Overall, these studies build upon a steadfast trajectory that aims to solve the monumentally daunting challenge of finding a cure for many types of cancer by modulating autophagy either through inhibition or induction.

Keywords: Autophagy; Cancer; Chaperone-mediated autophagy; History; Selective autophagy; Treatment.

Fig. 1.

Three different types of autophagy. (A) Macroautophagy can be nonselective or selective. In the former, substrates may be engulfed randomly in bulk. In selective macroautophagy, specific cargo, such as ribosomes, mitochondria, protein aggregates and peroxisomes, are recognized by cargo receptors that can associate with LC3. (B) Microautophagy involves the direct uptake of cargo through the invagination of the lysosomal membrane. (C) Chaperone-mediated autophagy involves the direct translocation of an unfolded protein substrate across the lysosome via HSPA8 and the LAMP2A receptor. All three processes lead to the breakdown of cargo within the lysosome and the subsequent efflux of cellular building blocks back to the cytosol for use. See the text for details.

Fig. 2.

Macroautophagy is a multi-step process. Following induction of the ULK1/2 complex, nucleation of the phagophore occurs. Expansion of the phagophore is facilitated by the class III PtdIns3K complex (PtdIns3K), the ATG9A system, the ATG12–ATG5-ATG16L1 complex and LC3/GABARAP conjugation system. Eventually, the expanding membrane closes around its cargo to form an autophagosome and LC3-II is cleaved from the outer membrane of this structure. Subsequently, the outer membrane of the autophagosome fuses with the lysosomal membrane to form an autolysosome. The contents of the autolysosome are then degraded and exported back into the cytoplasm for reuse by the cell. See the text for details.

Fig. 3.

This timeline depicts a curated set of landmark discoveries in autophagy-related cancer research.