Fatty Acid Synthase Inhibition in Human Breast Cancer Cells Leads to Malonyl-CoA-Induced Inhibition of Fatty Acid Oxidation and Cytotoxicity

Thupari, Jagan N.; Pinn, Michael L.; Kuhajda, Francis P.

doi:10.1006/bbrc.2001.5146

Cited by 175 publications

(139 citation statements)

References 18 publications

Supporting

Mentioning

124

Contrasting

Unclassified

Order By: Relevance

“…26,[51][52][53] Reduced carnitine palmitoyltransferase-1 interaction with the antiapoptotic protein Bcl-2 54 or palmitoyltransferase-1 inhibition-induced accumulation of ceramide, a sphingolipid implicated in apoptosis through death inducers and the extrinsic pathway of apoptosis, 26 were previously suggested to explain the pro-apoptotic effect of FASN blockage. The results in this study presented show activation of the intrinsic pathway of apoptosis by the release of cytochrome c from B16-F10 melanoma cell mitochondria following FASN chemical inhibition or knockdown, which was associated with caspase-9 and -3 activation in agreement with previous findings.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of fatty acid synthase in melanoma cells activates the intrinsic pathway of apoptosis

Zecchin

Rossato

Raposo

et al. 2011

Laboratory Investigation

View full text Add to dashboard Cite

Fatty acid synthase (FASN) is the metabolic enzyme responsible for the endogenous synthesis of the saturated long-chain fatty acid, palmitate. In contrast to most normal cells, FASN is overexpressed in a variety of human cancers, including cutaneous melanoma, in which its levels of expression are associated with tumor invasion and poor prognosis. We have previously shown that FASN inhibition with orlistat significantly reduces the number of spontaneous mediastinal lymph node metastases following the implantation of B16-F10 mouse melanoma cells in the peritoneal cavity of C57BL/6 mice. In this study, we investigate the biological mechanisms responsible for the FASN inhibition-induced apoptosis in B16-F10 cells. Both FASN inhibitors, cerulenin and orlistat, significantly reduced melanoma cell proliferation and activated the intrinsic pathway of apoptosis, as demonstrated by the cytochrome c release and caspase-9 and -3 activation. Further, apoptosis was preceded by an increase in both reactive oxygen species production and cytosolic calcium concentrations and independent of p53 activation and mitochondrial permeability transition. Taken together, these findings demonstrate the mitochondrial involvement in FASN inhibition-induced apoptosis in melanoma cells.

show abstract

Section: Discussionmentioning

confidence: 99%

Inhibition of fatty acid synthase in melanoma cells activates the intrinsic pathway of apoptosis

Zecchin

Rossato

Raposo

et al. 2011

Laboratory Investigation

View full text Add to dashboard Cite

show abstract

“…The mechanism(s) underlying malignant cell cytotoxicity following FAS inhibition has been studied in several cancer cell lines. FAS inhibition can cause accumulation of malonyl-CoA, which leads to inhibition of carnitine palmitoyltransferase-1 and, indirectly, the fatty acid oxidation pathway (Thupari et al, 2001). Rapid accumulation of malonyl-CoA was observed after FAS inhibition .…”

Section: Hindiii (557)mentioning

confidence: 99%

Fatty acid synthase: a novel target for antiglioma therapy

et al. 2006

View full text Add to dashboard Cite

High levels of fatty acid synthase (FAS) expression have been observed in several cancers, including breast, prostate, colon and lung carcinoma, compared with their respective normal tissue. We present data that show high levels of FAS protein in human and rat glioma cell lines and human glioma tissue samples, as compared to normal rat astrocytes and normal human brain. Incubating glioma cells with the FAS inhibitor cerulenin decreased endogenous fatty acid synthesis by approximately 50%. Cell cycle analysis demonstrated a time-and dose-dependent increase in S-phase cell arrest following cerulenin treatment for 24 h. Further, treatment with cerulenin resulted in time-and dose-dependent decreases in glioma cell viability, as well as reduced clonogenic survival. Increased apoptotic cell death and PARP cleavage were observed in U251 and SNB-19 cells treated with cerulenin, which was independent of the death receptor pathway. Overexpressing Bcl-2 inhibited cerulenin-mediated cell death. In contrast, primary rat astrocytes appeared unaffected. Finally, RNAi-mediated knockdown of FAS leading to reduced FAS enzymatic activity was associated with decreased glioma cell viability. These findings suggest that FAS might be a novel target for antiglioma therapy.

show abstract

“…Furthermore, besides lipogenesis, breakdown of fatty acids can also regulate fatty acid metabolism through carnitine palmitoyltransferase-1 (CPT-1). It has been observed that inhibition of CPT-1 with etomoxir resulted in cerulenine-like effects with downregulation of FA synthesis [173]. Therefore, there is an increasing interest in identifying and developing new anti-tumor compounds that modulate FA metabolism.…”

Section: Targeting De Novo Fa Synthesismentioning

confidence: 99%