Excess Polyunsaturated Fatty Acids Induce Death in Acidic Cancer Cells

Therapeutic modalities that exploit tumor metabolic reprogramming are of increasing interest, with researchers exploring dietary modification and supplementation to control nutrient utilization in tumors. Although an association has been reported between consumption of dietary omega-3 (n-3) polyunsaturated fats (PUFA) and lower cancer-associated deaths in certain cohorts, the potential efficacy of dietary PUFAs is not well understood. To investigate how supplementation of specific PUFAs might exert cytotoxic effects, Dierge and colleagues cultured cancer cells in acidic (pH 6.5) or neutral (pH 7.4) media to mimic tumor acidosis and found that acid-adapted cancer cells had a higher capacity to accumulate n-3 and n-6 PUFAs into lipid droplets. Long-term exposure to PUFAs inhibited cancer cell growth in monolayer culture, whereas PUFAs caused cytotoxicity in three-dimensional tumor spheroids, in which cells at the spheroid core were exposed to acidosis. Culturing spheroids in media containing bicarbonate or buffered at a more alkaline pH abrogated the cytotoxic effect of PUFAs. PUFA exposure increased levels of lipid peroxidation, suggesting that excess PUFA uptake led to cytotoxicity attributable to lipid peroxidation damage. Given that lipid peroxidation is associated with ferroptosis, the ferroptosis inducer erastin enhanced PUFA-mediated cytotoxicity, whereas ferroptosis inhibitors including ferrostatin-1 inhibited cytotoxicity, supporting ferroptosis as the primary mode of cell death. To understand the function of PUFA accumulation, lipid droplet formation was blocked by diacylglycerol O-acyltransferase 1 inhibitors (DGAT1i), which prevented PUFA buffering and therefore increased lipid peroxidation. Indeed, DGAT1i enhanced the anticancer effects of n-3 or n-6 PUFAs, increasing ferroptosis-dependent cytotoxicity. In a murine xenograft model of colorectal carcinoma, mice were fed isocaloric diets based on olive oil (monounsaturated fatty acid) or concentrated fish oil (PUFA). A PUFA-rich diet inhibited tumor growth and extended survival, whereas the combination of a PUFA-rich diet and DGAT1i administration enhanced these phenotypes. Together, this work highlights dietary n-3 PUFA supplementation as a potential anticancer strategy to combine with other pharmacologic approaches.

Dierge E, Debock E, Guilbaud C, Corbet C, Mignolet E, Mignard L, et al. Peroxidation of n-3 and n-6 polyunsaturated fatty acids in the acidic tumor environment leads to ferroptosis-mediated anticancer effects. Cell Metab 2021 Jun 11 [Epub ahead of print].

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