Autophagy on acid

Abstract

The microenvironment of solid tumors tends to be more acidic (6.5–7.0) than surrounding normal (7.2–7.4) tissue. Chaotic vasculature, oxygen limitation and major metabolic changes all contribute to the acidic microenvironment. We have previously proposed that low extracellular pH (pHe) plays a critical role in the development and progression of solid tumors. While extracellular acidosis is toxic to most normal cells, cancer cells can adapt and survive under this harsh condition. In this study, we focused on identifying survival strategies employed by cancer cells when challenged with an acidic pHe (6.6–6.7) either acutely or for many generations. While acutely acidic cells did not grow, those acclimated over many generations grew at the same rate as control cells. We observed that these cells induce autophagy in response to acidosis both acutely and chronically, and that this adaptation appears to be necessary for survival. Inhibition of autophagy in low pH cultured cells results in cell death. Histological analysis of tumor xenografts reveals a strong correlation of LC3 protein expression in regions projected to be acidic. Furthermore, in vivo buffering experiments using sodium bicarbonate, previously shown to raise extracellular tumor pH, decreases LC3 protein expression in tumor xenografts. These data imply that autophagy can be induced by extracellular acidosis and appears to be chronically employed as a survival adaptation to acidic microenvironments.

Keywords: :

• tumor microenvironment
• acidosis
• autophagy
• carcinogenesis
• somatic evolution

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Acknowledgments

This work is supported by RO1 CA077575 and U54CA143970 (R.J.G.).