Therapeutic exploitation of tumor addiction to fatty acids under acidosis

Abstract

Acidosis is considered as a hallmark of the tumor microenvironment. Indeed, extracellular pH has been determined in a wide variety of cancers to be significantly more acidic than in normal tissues. Recently, we identified an acidosis-driven metabolic shift from a largely glycolytic metabolism towards significant alterations in fatty acid (FA) metabolism allowing the concomitance of FA oxidation and glutamine-fueled FA synthesis. In this study, we aim to take advantage of this lipid addiction of acidosis-adapted cancer cells to evaluate the possibility to force these cells to take up potentially cytotoxic FA. Growth inhibitory effects were observed with omega-6 (n-6) and omega-3 (n-3) polyunsaturated FA (PUFA) in proportion to the number of unsaturations for both PUFA. More precisely, while short-chain PUFA had only minor effects on cancer cell growth, long-chain PUFA, such as docosapentaenoic acid (DPA n-6) and docosahexaenoic acid (DHA n-3) induced specific cytotoxic effects on acidosis-adapted cells but not on parental cells (at pH 7.4). Furthermore, we found that PUFA are less (rapidly) metabolized than corresponding saturated FA and block respiration fueled by saturated FA in acidosis-adapted cancer cells. Finally, we showed that 3D tumor spheroid growth was severely impaired upon treatment with DPA n-6 and DHA n-3. This growth inhibitory effect was observed only after 4 to 7 days of PUFA administration, which corresponds to the timing for acidosis development. The above effects suggest that PUFA administration could represent a modality to block tumor growth and disease progression in vivo