Autophagy Modulation in Cancer: Current Knowledge on Action and Therapy

Abstract

In the last two decades, accumulating evidence pointed to the importance of autophagy in various human diseases. As an essential evolutionary catabolic process of cytoplasmatic component digestion, it is generally believed that modulating autophagic activity, through targeting specific regulatory actors in the core autophagy machinery, may impact disease processes. Both autophagy upregulation and downregulation have been found in cancers, suggesting its dual oncogenic and tumor suppressor properties during malignant transformation. Identification of the key autophagy targets is essential for the development of new therapeutic agents. Despite this great potential, no therapies are currently available that specifically focus on autophagy modulation. Although drugs like rapamycin, chloroquine, hydroxychloroquine, and others act as autophagy modulators, they were not originally developed for this purpose. Thus, autophagy may represent a new and promising pharmacologic target for future drug development and therapeutic applications in human diseases. Here, we summarize our current knowledge in regard to the interplay between autophagy and malignancy in the most significant tumor types: pancreatic, breast, hepatocellular, colorectal, and lung cancer, which have been studied in respect to autophagy manipulation as a promising therapeutic strategy. Finally, we present an overview of the most recent advances in therapeutic strategies involving autophagy modulators in cancer.

Role of alternative splicing signatures in the prognosis of glioblastoma

“…Autophagy is an intracellular degradative process, which exerts pivotal functions in maintaining metabolism and homeostasis . In cancer biology, autophagy may exert dual effects in tumor promotion and suppression . Targeting autophagy has been a focus in searching for novel therapies for cancers .…”

Neuroprotective effects of curcumin through autophagy modulation

“…During macroautophagy, portions of cytoplasm are sequestered to form a double‐membrane structure, phagophore, which in a selective or non‐selective manner engulfs cytoplasmic cargo destined for degradation. As the phagophore forms and expands, it gradually matures and seals, building a closed autophagosome which fuses with a late endosome or lysosome to form an autolysosome . This autolysosome degrades the autophagosome‐trapped cargo.…”

“…This autolysosome degrades the autophagosome‐trapped cargo. Finally, degradation products are recycled via cellular anabolic reactions . Conversely, in microautophagy, the lysosomal membrane itself invaginates the cytoplasmic cargo, leading to degradation in the lysosomal lumen.…”

“…Chaperone‐mediated autophagy is a selective autophagy which requires a cytosolic chaperone, specifically heat shock cognate protein of 70 kDa (HSC70), to recognize the cytosolic target protein in order to initiate autophagy. The cytosolic target protein must contain a KFERQ or KFERQ‐like sequence motif to interact with the HSC70 protein complex and the lysosome‐associated membrane glycoprotein type 2A (LAMP2A), enabling the delivery of the target proteins into the lysosomal lumen …”

“…As the phagophore forms and expands, it gradually matures and seals, building a closed autophagosome which fuses with a late endosome or lysosome to form an autolysosome. 9 This autolysosome degrades the autophagosome-trapped cargo. Finally, degradation products are recycled via cellular anabolic reactions.…”