Abstract
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.
Highlights
In contrast to normal tissues that mainly utilize exogenetic lipids, cancers cells tend to undergo active de novo lipogenesis [1, 2]
Our results reveal that Fatty acid synthase (FAS) inhibition perturbs the homeostasis of NADPH/NADP+, which results in the generation of reactive oxygen species (ROS) and is responsible for FAS inhibition-induced apoptosis
Our data suggest that FAS inhibition-induced apoptosis most likely results from NADPH accumulation
Summary
In contrast to normal tissues that mainly utilize exogenetic lipids, cancers cells tend to undergo active de novo lipogenesis [1, 2]. FAS is a potential target for cancer therapy, and several small-molecule FAS inhibitors, such as cerulenin and orlistat, are extensively studied. Orlistat is an irreversible inhibitor forming a covalent adduct with the active serine of thioesterase domain in FAS [9]. These FAS inhibitors induces apoptosis in cancer cells both in vivo and in vitro and have been utilized as potential treatments for cancers [3, 10, 11]. The detailed mechanism by which FAS inhibition induces apoptosis still remains to be explored
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