Abstract
Autophagy, a major clearance route for many long-lived proteins and organelles, has long been implicated in cancer development. Myc is a proto-oncogene often found to be deregulated in many cancers, and thus is an attractive target for design of cancer therapy. Therefore, understanding the relationship between anti-Myc strategies and autophagy will be important for development of effective therapy. Here, we show that Myc depletion inhibits autophagosome formation and impairs clearance of autophagy substrates. Myc suppression has an inhibitory effect on autophagy via reduction of c-Jun N-terminal kinase 1 (JNK1) and B-cell lymphoma 2 (Bcl2) phosphorylation. Additionally, the decrease in JNK1 phosphorylation observed with Myc knockdown is associated with a reduction in ROS production. Our data suggest that targeting Myc in cancer therapy might have the additional benefit of inhibiting autophagy in the case of therapy resistance associated with chemotherapy-induced autophagy.
Highlights
IntroductionMacroautophagy (hereafter called autophagy) is an evolutionarily conserved process for bulk degradation of cytoplasmic contents
Macroautophagy is an evolutionarily conserved process for bulk degradation of cytoplasmic contents
LC3-II is the only known protein to associate with autophagosomes, and it is widely accepted as a marker for monitoring autophagy [24]
Summary
Macroautophagy (hereafter called autophagy) is an evolutionarily conserved process for bulk degradation of cytoplasmic contents. Autophagy is maintained at a basal level [1], where it is essential for quality control of the cytoplasmic environment through the maintenance of energy balance and by eliminating dysfunctional organelles and aggregate-prone proteins. Under stress conditions, such as starvation and hypoxia, autophagy is induced as an adaptive response, and drives the catabolism of proteins, lipids and carbohydrates for de novo biosynthesis of biomacromolecules, which enables cells to meet their metabolic and energy demands [2]. This, in turn, activates autophagy, since Beclin 1 activates the lipid kinase Vps, vacuolar protein sorting 34, which generates phosphatidylinositol 3-phosphate to enhance autophagosome formation
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