Mechanism of apoptosis induced by the inhibition of fatty acid synthase in breast cancer cells.

Abstract

Fatty acid synthase (FAS) has been found to be overexpressed in a wide range of epithelial tumors, including breast cancer. Pharmacologic inhibitors of FAS cause apoptosis of breast cancer cells and result in decreased tumor size in vivo. However, how the inhibition of FAS induces apoptosis in tumor cells remains largely unknown. To understand the apoptotic pathway resulting from direct inhibition of FAS, we treated breast tumor cells with or without FAS small interfering RNA (siRNA) followed by a microarray analysis. Our results indicated that the proapoptotic genes BNIP3, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), and death-associated protein kinase 2 (DAPK2) were significantly up-regulated on direct inhibition of the FAS gene. We also found that the knockdown of FAS expression significantly increased ceramide level in the tumor cells, and this increase was abrogated by acetyl-CoA carboxylase inhibitor. In addition, carnitine palmitoyltransferase-1 (CPT-1) inhibitor up-regulated the ceramide and BNIP3 levels in these cells, whereas treatment of tumor cells with FAS siRNA in the presence of a ceramide synthase inhibitor abrogated the up-regulation of BNIP3 and inhibited apoptosis. Furthermore, we found that treatment of cells with BNIP3 siRNA significantly counteracted the effect of FAS siRNA-mediated apoptosis. Consistent with these results, a significant inverse correlation was observed in the expression of FAS and BNIP3 in clinical samples of human breast cancer. Collectively, our results indicate that inhibition of FAS in breast cancer cells causes accumulation of malonyl-CoA, which leads to inhibition of CPT-1 and up-regulation of ceramide and induction of the proapoptotic genes BNIP3, TRAIL, and DAPK2, resulting in apoptosis.

• Authors: Sucharita Bandyopadhyay, Rui Zhan, Ying Wang, Sudha K Pai, Shigeru Hirota, Sadahiro Hosobe, Yukio Takano, Ken Saito, Eiji Furuta, Megumi Iiizumi, Sonia Mohinta, Misako Watabe, Charles Chalfant, Kounosuke Watabe
• Journal: Cancer research (Cancer Res) Vol. 66 Issue 11 Pg. 5934-40 (Jun 01 2006) ISSN: 0008-5472 [Print] United States
• PMID: 16740734 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Apoptosis Regulatory Proteins
• BNIP3 protein, human
• Membrane Glycoproteins
• Membrane Proteins
• Proto-Oncogene Proteins
• RNA, Small Interfering
• TNF-Related Apoptosis-Inducing Ligand
• TNFSF10 protein, human
• Tumor Necrosis Factor-alpha
• Fatty Acid Synthases
• DAPK2 protein, human
• Death-Associated Protein Kinases
• Calcium-Calmodulin-Dependent Protein Kinases

Topics

• Apoptosis (genetics, physiology)
• Apoptosis Regulatory Proteins (genetics)
• Breast Neoplasms (enzymology, genetics, pathology)
• Calcium-Calmodulin-Dependent Protein Kinases (genetics)
• Cell Line, Tumor
• Death-Associated Protein Kinases
• Fatty Acid Synthases (antagonists & inhibitors, genetics)
• Humans
• Membrane Glycoproteins (genetics)
• Membrane Proteins (biosynthesis, genetics)
• Proto-Oncogene Proteins (biosynthesis, genetics)
• RNA, Small Interfering (genetics)
• TNF-Related Apoptosis-Inducing Ligand
• Tumor Necrosis Factor-alpha (genetics)
• Up-Regulation