Autophagy paradox: Genetic and epigenetic control of autophagy in cancer progression.

Autophagy is a highly regulated, evolutionarily conserved process of self-digestion controlled by autophagy-related (ATG) genes. It involves the lysosomal degradation of cargoes, including cytoplasmic organelles, misfolded proteins, and toxic aggregates, to enrich cellular nutrient pools and reduce oxidative stress. In normal cells, basal autophagy occurs to maintain cellular homeostasis, which changes during tumor initiation, progression, and malignant transformation.

mTOR inhibitors in targeting autophagy and autophagy-associated signaling for cancer cell death and therapy.

The mechanistic target of rapamycin (mTOR) is a protein kinase that plays a central regulatory switch to control multifaceted cellular processes, including autophagy. As a nutrient sensor, mTOR inhibits autophagy by phosphorylating and inactivating key regulators, including ULK1, Beclin-1, UVRAG, and TFEB, preventing autophagy initiation and lysosomal biogenesis. It also suppresses autophagy-related protein expression, prioritizing growth over cellular recycling.