The Role of Autophagy in Gastric Cancer Chemoresistance: Friend or Foe?

Abstract

Gastric cancer is the third most common cause of cancer-related death worldwide. Drug resistance is the main inevitable and vital factor leading to a low 5-year survival rate for patients with gastric cancer. Autophagy, as a highly conserved homeostatic pathway, is mainly regulated by different proteins and non-coding RNAs (ncRNAs) and plays dual roles in drug resistance of gastric cancer. Thus, targeting key regulatory nodes in the process of autophagy by small molecule inhibitors or activators has become one of the most promising strategies for the treatment of gastric cancer in recent years. In this review, we provide a systematic summary focusing on the relationship between autophagy and chemotherapy resistance in gastric cancer. We comprehensively discuss the roles and molecular mechanisms of multiple proteins and the emerging ncRNAs including miRNAs and lncRNAs in the regulation of autophagy pathways and gastric cancer chemoresistance. We also summarize the regulatory effects of autophagy inhibitor and activators on gastric cancer chemoresistance. Understanding the vital roles of autophagy in gastric cancer chemoresistance will provide novel opportunities to develop promising therapeutic strategies for gastric cancer.

Autophagy and Digestive Disorders: Advances in Understanding and Therapeutic Approaches

“…This refers to cell death induced by the activation of autophagy flux alone, with no other types of programmed cell death involved (Jung et al, 2020). Cancer cells at risk of cell death could stimulate protective autophagy against the stress induced by chemotherapy, resulting in chemoresistance (Jing et al, 2020;Xu et al, 2020a). Conversely, direct and strong stimulation of autophagy by specific chemotherapies could induce autophagic cell death, highlighting the dual nature of autophagy.…”

“…Conversely, direct and strong stimulation of autophagy by specific chemotherapies could induce autophagic cell death, highlighting the dual nature of autophagy. Autophagy itself can reverse chemoresistance by mediating apoptosis and/or inhibiting epithelial-mesenchymal transition (EMT) (Xu et al, 2020a). The outcome of the autophagy process varies depending on the stress level and stage of the cancer.…”

“…Nevertheless, the laboratory investigations into drugs targeting or mediating autophagy in cancer therapy are attracting increased attention; novel compounds and pathways have been discovered. For instance, natural products, such as flavonoids, alkaloids, terpenoids, and coumarins, have been reported as potential autophagy inhibitors and activators and as agents reversing multidrug resistance in gastric cancer (Xu et al, 2020a). Furthermore, pectolinarigenin, which is a natural flavonoid present in Cirsium chanroenicum and citrus fruits, has been shown to induce autophagy-and apoptosis-related cell death in the AGS and MKN28 human gastric cancer cell lines (Lee et al, 2018).…”

PROTAC: An Effective Targeted Protein Degradation Strategy for Cancer Therapy

“…In particular, the development of small molecule kinase inhibitors has become one of the most widely pursued fields in the process of drug discovery and has made great achievements in cancer treatment (Wu et al, 2015). However, after the success, the treatment strategy also faces the same problem of drug resistance as chemotherapy (Dong et al, 2020;Xu et al, 2020). Therefore, drug resistance is the main limitation for cancer therapy and needs to be solved urgently.…”

Identification of an autophagy-related gene expression signature for colorectal cancer

“…Autophagy abnormality participates in the development of many diseases, including immune dysfunction, neurodegenerative disease, chronic disease and tumor (Ait-Aissa et al 2020;Li et al 2020;Zhao and Zhang 2019). However, it still remains controversial what role autophagy plays in tumor (Levy et al 2017;Xu et al 2020). In premalignant stage, stimulation of autophagy could prevent cancer development.…”