Fatty acid synthase (FASN) regulates the mitochondrial priming of cancer cells

Abstract

Inhibitors of the lipogenic enzyme fatty acid synthase (FASN) have attracted much attention in the last decade as potential targeted cancer therapies. However, little is known about the molecular determinants of cancer cell sensitivity to FASN inhibitors (FASNis), which is a major roadblock to their therapeutic application. Here, we find that pharmacological starvation of endogenously produced FAs is a previously unrecognized metabolic stress that heightens mitochondrial apoptotic priming and favors cell death induction by BH3 mimetic inhibitors. Evaluation of the death decision circuits controlled by the BCL-2 family of proteins revealed that FASN inhibition is accompanied by the upregulation of the pro-death BH3-only proteins BIM, PUMA, and NOXA. Cell death triggered by FASN inhibition, which causally involves a palmitate/NADPH-related redox imbalance, is markedly diminished by concurrent loss of BIM or PUMA, suggesting that FASN activity controls cancer cell survival by fine-tuning the BH3 only proteins-dependent mitochondrial threshold for apoptosis. FASN inhibition results in a heightened mitochondrial apoptosis priming, shifting cells toward a primed-for-death state “addicted” to the anti-apoptotic protein BCL-2. Accordingly, co-administration of a FASNi synergistically augments the apoptosis-inducing activity of the dual BCL-XL/BCL-2 inhibitor ABT-263 (navitoclax) and the BCL-2 specific BH3-mimetic ABT-199 (venetoclax). FASN inhibition, however, fails to sensitize breast cancer cells to MCL-1- and BCL-XL-selective inhibitors such as S63845 and A1331852. A human breast cancer xenograft model evidenced that oral administration of the only clinically available FASNi drastically sensitizes FASN-addicted breast tumors to ineffective single-agents navitoclax and venetoclax in vivo. In summary, a novel FASN-driven facet of the mitochondrial priming mechanistically links the redox-buffering mechanism of FASN activity to the intrinsic apoptotic threshold in breast cancer cells. Combining next-generation FASNis with BCL-2-specific BH3 mimetics that directly activate the apoptotic machinery might generate more potent and longer-lasting antitumor responses in a clinical setting.

Periostin facilitates ovarian cancer recurrence by enhancing cancer stemness

“…Our data also provide evidence for a communication between fatty acid metabolism inside and outside of cancer cells. A recent study suggested that FASN inhibition increases mitochondrial priming and enhances breast cancer cell sensitivity to BCL2-targeting BH3 mimetics which may directly activate the apoptotic machinery and generate more potent and longer-lasting antitumor responses in a clinical setting 46 . We showed that OC cells are more resistant to the FASN inhibitor Cerulenin when they are cultured in the conditioned medium with higher POSTN.…”

Fatty acid metabolism-related signature predicts survival in patients with clear cell renal carcinoma

“…Lipid metabolism has attracted significant attention in cancer research in recent years because it provides a novel connection between blockers of lipid metabolism and inhibitors of tumor growth and invasion [ 17 ]. FASN regulates fatty acid metabolism and plays a critical role in the growth and tissue invasion by many cancers [ 18 , 19 ]. We found a few studies providing deep analysis of the role of FASN in clear cell renal carcinoma development.…”

Targeting Mitochondria with ClpP Agonists as a Novel Therapeutic Opportunity in Breast Cancer

“…FASN is overexpressed in 70% of operable TNBC and is associated with poor prognosis [ 117 , 118 ]. FASN regulates Bcl-2 family proteins and controls breast cancer cell survival [ 119 ]. Acetyl-CoA synthetase 2 (ACSS2) is amplified in breast cancers and targeting ACSS2 impaired tumor growth in TNBC [ 120 , 121 ].…”