Selective Autophagy Regulates Cell Cycle in Cancer Therapy

Abstract

Aberrant function of cell cycle regulators results in uncontrolled cell proliferation, making them attractive therapeutic targets in cancer treatment. Indeed, survival of many cancers exclusively relies on these proteins, and several specific inhibitors are in clinical use. Although the ubiquitin-proteasome system is responsible for the periodic quality control of cell cycle proteins during cell cycle progression, increasing evidence clearly demonstrates the intimate interaction between cell cycle regulation and selective autophagy, important homeostasis maintenance machinery. However, these studies have often led to divergent rather than unifying explanations due to complexity of the autophagy signaling network, the inconsistent functions between general autophagy and selective autophagy, and the different characteristics of autophagic substrates. In this review, we highlight current data illustrating the contradictory and important role of cell cycle proteins in regulating autophagy. We also focus on how selective autophagy acts as a central mechanism to maintain orderly DNA repair and genome integrity by degrading specific cell cycle proteins, regulating cell division, and promoting DNA damage repair. We further discuss the ways in which selective autophagy may impact the cell cycle regulators, since failure to appropriately remove these can interfere with cell death-related processes, including senescence and autophagy-related cell death. Imbalanced cell proliferation is typically utilized by cancer cells to acquire resistance. Finally, we discuss the possibility of a potent anticancer therapeutic strategy that targets selective autophagy or autophagy and cell cycle together.

H. pyloriinfection inhibits autophagy to aggravate DNA damage by p62-mediated Rad51 ubiquitination

“…These findings suggest that dysregulated DNA damage response to H. pylori infection is attributed to altered cell cycle progression. This premise is supported by previous data the interaction between autophagy and regulation of cell cycle (Zheng, He et al, 2019). Taken together, we hypothesize that early infection with H. pylori induced DSBs, which can be sufficiently repaired by concurrently induced autophagy.…”

Restoration of Autophagic Flux Rescues Oxidative Damage and Mitochondrial Dysfunction to Protect against Intervertebral Disc Degeneration

“…Autophagy, which is highly conserved in all eukaryotes, not only is the major intracellular degradation system through which damaged organelles and proteins are degraded in lysosomes but also is an active recycling system that produces materials and energy for the renovation and homeostasis of cells [10]. The term "autophagic flux" reflects the completion of the entire dynamic process of autophagosome formation and then fusion with lysosomes, subsequent degradation of cargo, and release of degradation products [11].…”

Selective degradation of IKKα by autophagy is essential for arsenite-induced cancer cell apoptosis

“…However, growing evidence support that autophagic degradation is also highly selective. The selectivity of autophagic sequestration towards intracellular pathogens, damaged organelles, cellular structures, protein aggregates or specific soluble proteins are important for cell functions 4,5 . The discovery and characterization of autophagic cargo receptors such as SQSTM1/p62, NBR1, NDP52, Optineurin, NIX, etc., has provided mechanistic insight into selective autophagy.…”