Dietary omega 6/3 fats and aspirin govern PI3Ka-induced oncogenicity

Abstract

Oncogenic mutations in PI3KCA, the gene encoding the p110a catalytic subunit of PI3K, represent one of the most frequent genetic alterations in human cancer. Although multiple inhibitors of the PI3K/AKT/mTOR pathway have entered clinical trials, the majority have been associated with drug resistance and/or limited efficacy due to dose-limiting toxicities, highlighting the need for the identification of more effective anti-cancer therapies. Aspirin is one of the widely used non-steroidal anti-inflammatory drugs as an effective analgesic, antipyretic and cardiovascular prophylactic agent. Several studies have demonstrated an intriguing connection between aspirin intake and higher anti-cancer activity in PI3KCA mutant tumours, however the mechanistic basis behind this association is still obscure. Here. we show that aspirin treatment inhibits cPLA2 activity via promoting its ascetylation, resulting in a concomitant decrease in arachidonic acid production. Oncogenic PIK3CA renders cells more sensitive to aspirin treatment, and this effect was significantly more pronounced when given alongside a diet with a "healthy" ratio of omega-6/omega-3 fatty acids. Overall, these data identify a COX-independent role for aspirin in suppressing arachidonic acid metabolism and support the combination of balancing omega-6/omega-3 fats with aspirin as an effective therapeutic strategy for targeting PI3KCA mutant tumours.