The interplay between autophagy and tumorigenesis: exploiting autophagy as a means of anticancer therapy

Abstract

In wild-type cells, autophagy represents a tumour-suppressor mechanism, and dysfunction of the autophagy machinery increases genomic instability, DNA damage, oxidative stress and stem/progenitor expansion, which are events associated with cancer onset. Autophagy occurs at a basal level in all cells depending on cell type and cellular microenvironment. However, the role of autophagy in cancer is diverse and can promote different outcomes even in a single tumour. For example, in hypoxic tumour regions, autophagy emerges as a protective mechanism and allows cancer cell survival. By contrast, in cancer cells surrounding the tumour mass, the induction of autophagy by radio-or chemotherapy promotes cell death and significantly reduces the tumour mass. Importantly, inhibition of autophagy compromises tumorigenesis by mechanisms that are not entirely understood. The aim of this review is to explain the apparently contradictory role of autophagy as a mechanism that both promotes and inhibits tumorigenesis using different models. The induction/inhibition of autophagy as a mechanism for cancer treatment is also discussed.

Mitochondrial dysfunction and potential anticancer therapy

“…We have shown that inhibition of protein synthesis may decrease ROS levels induced by aminoglycosides . Moreover, autophagy can regulate mitochondrial ΔΨ m and intracellular calcium . 6, Since Ca 2+ from the ER may transfer to mitochondria and increase ROS, one can speculate that antibiotics may increase ROS and induce autophagy by mobilizing calcium.…”

“…13 Moreover, autophagy can regulate mitochondrial ΔΨ m and intracellular calcium. 1876,187 Since Ca 2+ from the ER may transfer to mitochondria and increase ROS, 155,156 one can speculate that antibiotics may increase ROS and induce autophagy by mobilizing calcium. Mitophagy coupled with mitochondrial remodeling can unite all these processes with MDF.…”

Inhibition of Cathepsin D (CTSD) enhances radiosensitivity of glioblastoma cells by attenuating autophagy

“…Dysfunction of autophagy increases genomic instability, DNA damage, oxidative stress, and stem/progenitor cell expansion, which are all related to the occurrence of cancer. 9 Evidence shows that the inhibition of autophagy increases the efficiency of irradiation in xenograft models. 10 Furthermore, early clinical studies are paving the way for patients to provide autophagy inhibition as radiosensitization therapy.…”

Cordycepin‐induced unfolded protein response‐dependent cell death, and AKT/MAPK‐mediated drug resistance in mouse testicular tumor cells

“…In response to the environmental and genetic stresses, the UPR and autophagy are important mechanisms involved in the regulation of cellular stress responses, and both of them are interconnected . Many studies have focused on the UPR and autophagy as novel therapeutic targets for cancers because of the difference of metabolic mechanism and dependence on stress responses between normal and malignant cells . ER stress induces UPR by activating three master sensors located in the ER membrane: double‐stranded RNA‐activated protein kinase (PKR)‐like ER kinase (PERK), activating transcription factor 6 (ATF6), and inositol‐requiring enzyme 1 (IRE1) .…”

“…10,11 Many studies have focused on the UPR and autophagy as novel therapeutic targets for cancers because of the difference of metabolic mechanism and dependence on stress responses between normal and malignant cells. [12][13][14] ER stress induces UPR by activating three master sensors located in the ER membrane: double-stranded RNA-activated protein kinase (PKR)-like ER kinase (PERK), activating transcription factor 6 (ATF6), and inositol-requiring enzyme 1 (IRE1). [15][16][17] First, activation of PERK could result in the phosphorylation of eukaryotic translation initiation factor-2a and translation of the transcription factor ATF4, resulting in blocking protein translation and reducing the protein burden within the ER, cell cycle arrest, and thereby preventing further damage to the cells.…”