Modulating autophagy in cancer therapy: Advancements and challenges for cancer cell death sensitization

Abstract

Autophagy is a major protein degradation pathway capable of upholding cellular metabolism under nutrient limiting conditions, making it a valuable resource to highly proliferating tumour cells. Although the regulatory machinery of the autophagic pathway has been well characterized, accurate modulation of this pathway remains complex in the context of clinical translatability for improved cancer therapies. In particular, the dynamic relationship between the rate of protein degradation through autophagy, i.e. autophagic flux, and the susceptibility of tumours to undergo apoptosis remains largely unclear. Adding to inefficient clinical translation is the lack of measurement techniques that accurately depict autophagic flux. Paradoxically, both increased autophagic flux as well as autophagy inhibition have been shown to sensitize cancer cells to undergo cell death, indicating the highly context dependent nature of this pathway. In this article, we aim to disentangle the role of autophagy modulation in tumour suppression by assessing existing literature in the context of autophagic flux and cellular metabolism at the interface of mitochondrial function. We highlight the urgency to not only assess autophagic flux more accurately, but also to center autophagy manipulation within the unique and inherent metabolic properties of cancer cells. Lastly, we discuss the challenges faced when targeting autophagy in the clinical setting. In doing so, it is hoped that a better understanding of autophagy in cancer therapy is revealed in order to overcome tumour chemoresistance through more controlled autophagy modulation in the future.

Keywords: 3-MethylAdenine(3-MA) (PubChem CID: 1673); Apoptosis; Autophagy modulation; Bafilomycin A1 (PubChem CID: 6436223); Cancer metabolism; Cell death; Chemotherapeutic sensitization; Chloroquine (PubChem CID: 64927); Everolimus (PubChem CIDL: 6442177); Metformin (PubChem CID: 4091); Mitochondria; Perifosine (PubChem CID: 148177); Rapamycin (PubChem CID: 62969); Resveratrol (PubChem CID: 445154); Spermidine (PubChem CID: 1102); Suberoylanilide hydroxamic acid (SAHA) (PubChem CID: 5311).