Modulating Autophagy and the "Reverse Warburg Effect"

Abstract

Autophagy is a highly regulated cellular pathway for degrading longlived proteins and is the only known pathway for clearing cytoplasmic organelles. Autophagy is a major contributor to maintain cellular homeostasis and metabolism. The quality control of mitochondria is essential to maintain cell energy and this process appears to be achieved via autophagy. Warburg hypothesized that cancer growth is caused by the fact that tumor cells mainly generate energy by the non-oxidative breakdown of glucose. This cellular behavior relies on a respiratory impairment, characterized by a mitochondrial dysfunction, which results in a switch to glycolysis. Moreover, epithelial cancer cells may induce the Warburg effect in neighboring stromal fibroblasts in which autophagy was activated. Here, we introduce the autophagy process, its regulation, the selective pathways, and its role in cancer cell metabolism. We define the Warburg effect and the "reverse" hypothesis and we discuss the potential value of modulating autophagy. The association of the Warburg effect in tumor and stromal cells to cancer-related autophagy is of significant relevance in experimental therapeutics.