Role of SIRT3 and autophagy in the response of cancer cells to acidic pH

Acidosis is a well-known physico-chemical property of the tumor microenvironment. The release of lactate (the end product of glycolysis) together the hydratation of CO2 into bicarbonate and proton (by tumor cells that have access to O2) contribute to the acidification of the tumor microenvironment. Large amounts of lactate/H+ are also released by tumor cells exhibiting aerobic glycolysis (the so-called Warburg effect). Extracellular pH (pHe) has actually been determined in a wide variety of cancers to be significantly more acidic than in normal tissues, with values ranging from 5.9 to 7.2. Acidosis is known to contribute to the genetic instability of tumor cells and to profoundly alter their transcriptomic profile, leading to phenotypes that are particularly suited for survival and growth in an acidic environment. A low pHe has for instance a wide impact on cancer progression by promoting tumor cell migration, invasion, and metastasis and by stimulating angiogenesis. We show that the capacity of MDA-MB-231 to develop resistance to the acute extracellular acidification is associated with an increase in SIRT3 deacetylase protein leading to a raise in mitochondrial CA VB activity and expression. Concomitantly we have observed a decrease of autophagy, assessed through LC3II and ATG5 protein expression and TEM analysis. Moreover, SIRT3 overexpression significantly increased CA VB catalytic activity compared to WT and SIRT3-silenced cells thereby reducing the amount of lactate acid in growth medium. At the same time, SIRT3-dependent deacetylation increases the enzymatic activity of GDH when MDA-MB-231 cells are under low acute pHe confirming a role of SIRT3 in metabolism reprogramming. Further, the use of SIRT3 activators in the growth medium has shown an increase of the catalytic activity of SIRT3 and CA VB in MDA-MB-231 cells improving cellular response at low pHe, suggesting the potential therapeutic benefits of the SIRT3 inhibitors in pathologies associated with pH decrease.