Mitophagy and Reverse Warburg Effect: Metabolic Compartmentalization of Tumor Microenvironment

Abstract

‘The Warburg effect' is one of the aberrant glucose metabolism pathways in cancer cells that generate malignant phenotypes and promotes cancer progression. However, in the year 2009, a novel model called ‘two-compartment metabolic coupling' model or ‘the reverse Warburg effect' was proposed where the tumor stromal plays a crucial role in the process of tumor progression. Based on this new model, the present review summarizes the autophagic stroma model of cancer and multiple compartment model of tumor metabolism. Cancer-associated fibroblast cells in tumor microenvironment undergo aerobic glycolysis (the reverse Warburg effect) just like the cancer cells. Such a phenomenon is possible only due to the forced activation of glycolysis by decreasing the mitochondrial mass and/or generating dysfunctional mitochondria. The tumor stroma is often found with autophagic and mitophagic activities as evidenced by the higher expression of autophagic and mitophagic signature molecules. Moreover, caveolin-1 and hypoxia-inducible factor-1α play a fundamental role in governing the mitophagy-mediated occurrence of ‘reverse Warburg effect'. To the surprise, cancer stem cell also follows the same strategy to exploit the tumor stroma in order to derive high energy fuels for its survival and proliferation. Such parasitic energy-coupling between the cancer cell and cancer-associated fibroblasts makes the fibroblasts a metabolic slave. The metabolic coupling is the result of the paracrine regulation where oxidative stress generated in adjacent fibroblasts by the reactive oxygen species (ROS) produced by cancer cells along with the up-regulation of the oncometabolite transport process through various transporters. This review also discusses the paradigm shift from ‘the Warburg effect' to ‘the reverse Warburg effect'. It also describes the pivotal role of mitophagy in triggering the ‘the reverse Warburg effect'.