Lipogenesis mediated by OGR1 regulates metabolic adaptation to acid stress in cancer cells via autophagy

Malignant tumors exhibit altered metabolism resulting in a highly acidic extracellular microenvironment. Here we show that cytoplasmic lipid droplet (LD) accumulation, indicative of a lipogenic phenotype is a cellular adaption to extracellular acidity. LD marker PLIN2, is strongly associated with poor overall survival in breast cancer patients. Acid-induced LD accumulation is triggered by activation of the acid-sensing GPCR, OGR1 expressed highly in breast tumors. OGR1 depletion inhibited acid induced lipid accumulation while activation by synthetic agonist triggered LD formation. Inhibition of OGR1 downstream signaling abrogated the lipogenic phenotype which could be rescued with OGR1 ectopic expression. OGR1 depleted cells showed growth inhibition under acidic growth conditions in vitro and tumor formation in vivo. Isotope tracing showed that the source of lipid precursors is primarily autophagy-derived ketogenic amino acids. OGR1 depleted cells were defective in endoplasmic reticulum stress response and autophagy, hence failed to accumulate LDs affecting survival under acidic stress.