Autophagy modulation: a prudent approach in cancer treatment?

Abstract

Autophagy is a tightly controlled process comprising lysosomal degradation and recycling of cellular proteins and organelles. In cancer, its paradoxical dual role of cytoprotection and cytotoxicity is context-dependent and controversial. Autophagy primarily acts as a mechanism of tumour suppression, by maintenance of genomic integrity and prevention of proliferation and inflammation. This, combined with immune-surveillance capabilities and autophagy's implicated role in cell death, acts to prevent tumour initiation. However, established tumours exploit autophagy to survive cellular stresses in the hostile tumour microenvironment. This can lead to therapy resistance, one of the biggest challenges facing current anti-cancer approaches. Autophagy modulation is an exciting area of clinical development, attempting to harness this fundamental process as an anti-cancer strategy. Autophagy induction could potentially prevent tumour formation and enhance anti-cancer immune responses. In addition, drug-induced autophagy could be used to kill cancer cells, particularly those in which the apoptotic machinery is defective. Conversely, autophagy inhibition may help to sensitise resistant cancer cells to conventional chemotherapies and specifically target autophagy-addicted tumours. Currently, hydroxychloroquine is in phase I and II clinical trials in combination with several standard chemotherapies, whereas direct, deliberate autophagy induction remains to be tested clinically. More comprehensive understanding of the roles of autophagy throughout different stages of carcinogenesis has potential to guide development of novel therapeutic strategies to eradicate cancer cells.

The insufficiency of ATG4A in macroautophagy

“…The process culminates in autophagosome-lysosome fusion where degradation of cargo is driven by lysosomal hydrolases (2,9,10). Disruption of autophagy is associated with a multitude of diseases related to neurodegeneration, aging, microbial infection, and cancer (11)(12)(13).…”

Autophagy Regulation by the Translation Machinery and Its Implications in Cancer

“…Autophagy is also induced in response to several stressors, such as genotoxic compounds. In this case, autophagy maintains genome integrity and consequently, autophagy malfunctioning leads to tumorigenesis (31). Nevertheless, autophagy plays a dual role in cancer, as some cancerous cells acquire chemotherapy resistance through activating autophagy (32).…”

Dual targeting of NUAK1 and ULK1 using the multitargeted inhibitor MRT68921 exerts potent antitumor activities

“…However, the effectiveness of NUAK1-targeting therapies is still unsatisfactory 13 , which may be due to the inherent defense mechanisms of tumors, such as DNA damage repair, negative feedback, bypass signals, or autophagy 14 . Autophagy is an evolutionarily conserved intracellular catabolic process that is upregulated under conditions of perceived stress and in response to cellular damage 15 . Evidence has proven that autophagy is a protective effect in response to lethal oxidative stress 16 .…”