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Review
. 2011 Sep;10(9):1533-41.
doi: 10.1158/1535-7163.MCT-11-0047. Epub 2011 Aug 30.

The role of autophagy in cancer: therapeutic implications

Zhineng J Yang  1 , Cheng E Chee, Shengbing Huang, Frank A Sinicrope
Affiliations
Review

The role of autophagy in cancer: therapeutic implications

Zhineng J Yang et al. Mol Cancer Ther. 2011 Sep.

Abstract

Autophagy is a homeostatic, catabolic degradation process whereby cellular proteins and organelles are engulfed by autophagosomes, digested in lysosomes, and recycled to sustain cellular metabolism. Autophagy has dual roles in cancer, acting as both a tumor suppressor by preventing the accumulation of damaged proteins and organelles and as a mechanism of cell survival that can promote the growth of established tumors. Tumor cells activate autophagy in response to cellular stress and/or increased metabolic demands related to rapid cell proliferation. Autophagy-related stress tolerance can enable cell survival by maintaining energy production that can lead to tumor growth and therapeutic resistance. As shown in preclinical models, inhibition of autophagy restored chemosensitivity and enhanced tumor cell death. These results established autophagy as a therapeutic target and led to multiple early phase clinical trials in humans to evaluate autophagy inhibition using hydroxychloroquine in combination with chemotherapy or targeted agents. Targeting autophagy in cancer will provide new opportunities for drug development, because more potent and specific inhibitors of autophagy are needed. The role of autophagy and its regulation in cancer cells continues to emerge, and studies aim to define optimal strategies to modulate autophagy for therapeutic advantage.

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Figures

Figure 1
Figure 1. Overview of the Autophagy Pathway
The initiation of autophagy is controlled by the ULK1 kinase complex that integrates stress signals from mTORC1. When mTORC1 kinase activity is inhibited, autophagosome formation can occur from the phagophore and involves vacuolar sorting protein 34 (Vps34), a class III phosphoinositide 3-kinase (PI3K), that forms a complex with Beclin 1. Beclin 1 interacts with factors (Ambra, Bif1, Bcl-2) that modulate its binding to Vps34 whose lipid kinase activity is essential for autophagy. In addition to these two complexes, autophagosome formation requires the participation of two ubiquitin-like protein (Atg12 and LC3) conjugation systems that are essential for the formation of the phagophore. In addition, the LC3 system is required for autophagosome transport and maturation. Mature autophagosomes fuse their external membranes with those from lysosomes to degrade their cargo, and recycle essential biomolecules. Autophagy can be inhibited by drugs that target early or late stages in the pathway. Chloroquine (CQ) and hydroxychloroquine (HCQ) inhibit autophagy at a late stage by blocking lysosomal acidification resulting in an inability to digest its engulfed cargo.
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