Autophagy: A Versatile Player in the Progression of Colorectal Cancer and Drug Resistance

Abstract

Colorectal cancer (CRC) is among the topmost malignancies for both genders. Despite the high incidence rate and advances in diagnostic tools, treatment in many cases is still ineffective. Most cancerous lesions in CRC begin as benign, followed by the development of invasive forms and metastases. The development of CRC has been linked to defects in autophagy, which plays both a pro-and anti-tumor role and is mainly context-dependent. Autophagy suppression could enhance apoptosis via p53 activation, or autophagy also promotes tumor progression by maintaining tumor growth and increasing resistance to chemotherapy. Autophagy promotes the invasion and metastasis of CRC cells via increased epithelial-mesenchymal transition (EMT). Moreover, dysbiosis of gut microbiota upregulated autophagy and metastasis markers. Autophagy responses may also modulate the tumor microenvironment (TME) via regulating the differentiation process of several innate immune cells. Treatments that promote tumor cell death by stimulating or inhibiting autophagy could be beneficial if used as an adjunct treatment, but the precise role of various autophagy-modulating drugs in CRC patients is needed to be explored. In this article, we present an overview of the autophagy process and its role in the pathogenesis and therapeutic resistance of CRC. Also, we focused on the current understanding of the role of the EMT and TME, including its relation to gut microbiota and immune cells, in autophagic manipulation of CRC. We believe that there is a potential link between autophagy, TME, EMT, and drug resistance, suggesting that further studies are needed to explore this aspect.

Regulation of 5‐fluorodeoxyuridine monophosphate‐thymidylate synthase ternary complex levels by autophagy confers resistance to 5‐fluorouracil

“…Autophagy is a physiological process that maintains metabolism and cellular homeostasis by recycling damaged cellular components, e.g., abnormal proteins and/or damaged organelles. 26 , 34 , 35 The autophagic machinery is an intracellular degradation system mediated by the fusion of double‐membrane vesicles called autophagosomes, enveloping cytoplasmic components and organelles, to lysosomes to form autolysosomes, which degrade the encased contents. 26 , 34 , 35 In cancer biology, autophagy plays dual roles in tumor promotion and suppression, and contributes to cancer cell development and proliferation.…”

“… 26 , 34 , 35 The autophagic machinery is an intracellular degradation system mediated by the fusion of double‐membrane vesicles called autophagosomes, enveloping cytoplasmic components and organelles, to lysosomes to form autolysosomes, which degrade the encased contents. 26 , 34 , 35 In cancer biology, autophagy plays dual roles in tumor promotion and suppression, and contributes to cancer cell development and proliferation. 26 , 35 , 36 Several anticancer drugs, e.g., 5‐FU and cisplatin, can regulate autophagy.…”

“… 26 , 34 , 35 In cancer biology, autophagy plays dual roles in tumor promotion and suppression, and contributes to cancer cell development and proliferation. 26 , 35 , 36 Several anticancer drugs, e.g., 5‐FU and cisplatin, can regulate autophagy. 37 , 38 , 39 , 40 Similarly, several studies have reported that autophagy plays an important role in drug sensitivity and resistance to 5‐FU.…”

“…In addition, other known mechanisms underlying 5‐FU resistance include the perturbance of cell death, autophagy, altered epigenetic repression, and expression/functional changes in drug transporters and noncoding RNA 4,5,11 . Among these, autophagy has an important role in drug sensitivity and resistance to cancer chemotherapy with 5‐FU 5,26 . The inhibition of autophagy potentiates the cytotoxic effect of 5‐FU in CRC cells 27–29 .…”

“… 4 , 5 , 11 Among these, autophagy has an important role in drug sensitivity and resistance to cancer chemotherapy with 5‐FU. 5 , 26 The inhibition of autophagy potentiates the cytotoxic effect of 5‐FU in CRC cells. 27 , 28 , 29 The combination of 5‐FU and autophagy inhibitors, 3‐methyladenine (3‐MA) or chloroquine (CQ), inhibits 5‐FU‐induced autophagy and enhances 5‐FU induced tumor growth inhibition.…”