RNA interference-mediated silencing of the acetyl-CoA-carboxylase-alpha gene induces growth inhibition and apoptosis of prostate cancer cells.

Abstract

Overexpression of lipogenic enzymes is a common characteristic of many cancers. Thus far, studies aimed at the exploration of lipogenic enzymes as targets for cancer intervention have focused on fatty acid synthase (FAS), the enzyme catalyzing the terminal steps in fatty acid synthesis. Chemical inhibition or RNA interference (RNAi)-mediated knockdown of FAS consistently inhibits the growth and induces death of cancer cells. Accumulation of the FAS substrate malonyl-CoA has been implicated in the mechanism of cytotoxicity of FAS inhibition. Here, using RNAi technology, we have knocked down the expression of acetyl-CoA carboxylase-alpha (ACC-alpha), the enzyme providing the malonyl-CoA substrate. Silencing of the ACC-alpha gene resulted in a similar inhibition of cell proliferation and induction of caspase-mediated apoptosis of highly lipogenic LNCaP prostate cancer cells as observed after FAS RNAi. In nonmalignant cells with low lipogenic activity, no cytotoxic effects of knockdown of ACC-alpha or FAS were observed. These findings indicate that accumulation of malonyl-CoA is not a prerequisite for cytotoxicity induced by inhibition of tumor-associated lipogenesis and suggest that in addition to FAS, ACC-alpha is a potential target for cancer intervention.

• Authors: Koen Brusselmans, Ellen De Schrijver, Guido Verhoeven, Johannes V Swinnen
• Journal: Cancer research (Cancer Res) Vol. 65 Issue 15 Pg. 6719-25 (Aug 01 2005) ISSN: 0008-5472 [Print] United States
• PMID: 16061653 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• RNA, Small Interfering
• Malonyl Coenzyme A
• Fatty Acid Synthases
• Acetyl-CoA Carboxylase

Topics

• Acetyl-CoA Carboxylase (antagonists & inhibitors, biosynthesis, genetics, metabolism)
• Apoptosis (genetics)
• Cell Growth Processes (genetics)
• Cell Line, Tumor
• Fatty Acid Synthases (antagonists & inhibitors, genetics, metabolism)
• Gene Expression Regulation, Enzymologic
• Gene Expression Regulation, Neoplastic
• Gene Silencing
• Humans
• Male
• Malonyl Coenzyme A (metabolism)
• Prostatic Neoplasms (enzymology, genetics, pathology)
• RNA Interference
• RNA, Small Interfering (genetics)