Role of autophagy in suppression of inflammation and cancer

Abstract

Autophagy is a crucial component of the cellular stress adaptation response that maintains mammalian homeostasis. Autophagy protects against neurodegenerative and inflammatory conditions, aging, and cancer. This is accomplished by the degradation and intracellular recycling of cellular components to maintain energy metabolism and by damage mitigation through the elimination of damaged proteins and organelles. How autophagy modulates oncogenesis is gradually emerging. Tumor cells induce autophagy in response to metabolic stress to promote survival, suggesting deployment of therapeutic strategies to block autophagy for cancer therapy. By contrast, defects in autophagy lead to cell death, chronic inflammation, and genetic instability. Thus, stimulating autophagy may be a powerful approach for chemoprevention. Analogous to infection or toxins that create persistent tissue damage and chronic inflammation that increases the incidence of cancer, defective autophagy represents a cell-intrinsic mechanism to create the damaging, inflammatory environment that predisposes to cancer. Thus, cellular damage mitigation through autophagy is a novel mechanism of tumor suppression.

Figure 1

Mechanism by which autophagy defects promote cancer. Metabolic stress triggers oxidative damage, and p62 accumulation. Autophagy induction is responsible for the degradation of damaged cellular material, proteins, lipids, and organelles [23••]. In autophagy-defective cells, the degradation and recycling of cellular components is prevented, leading to persistence of p62, p62-containing protein aggregates and damaged mitochondria, and coordinate ROS production and activation of the DNA damage response. This alters the cellular proteome and gene expression, and leads to genome damage and chromosome instability, or cell death and inflammation. Evidence suggests that increased p62 accumulation, genome damage and inflammation may contribute to increased tumorigenesis in autophagy-defective cells and tissues.