NADPH accumulation is responsible for apoptosis in breast cancer cells induced by fatty acid synthase inhibition

Fatty acid synthase (FAS), as a key enzyme involved in de novo lipogenesis, is highly expressed in many cancers. FAS inhibition induces cell death in vivo and in vitro, rendering FAS as an attractive target for cancer therapy, but the defined mechanism is still not well understood. Herein, we confirmed that FAS was highly expressed in breast cancers and FAS inhibition by its inhibitors or knockdown induced apoptosis in breast cancer cells. Our results showed that a significantly high level of reactive oxygen species was induced but not responsible for apoptosis in breast cancer cells by FAS inhibition. Instead, NADPH accumulation resulting from FAS inhibition was found to stimulate NADPH oxidase to generate reactive oxygen species and highly associated with apoptosis induction. Suppression of NADPH oxidase almost totally blocked reactive oxygen species generation while significantly potentiated the in vitro and in vivo killing of breast cancers by FAS inhibition. Taken together, these data suggest that FAS plays a critical role in maintaining cellular redox homeostasis and its inhibition leads to NADPH accumulation-mediated apoptosis. Our finding may provide new insights into cancer metabolism and aid in designing effective anticancer treatments.