Acyl-CoA synthetase as a cancer survival factor: its inhibition enhances the efficacy of etoposide.

Abstract

Lipid metabolism is often elevated in cancer cells and plays an important role in their growth and malignancy. Acyl-CoA synthetase (ACS), which converts long-chain fatty acids to acyl-CoA, is overexpressed in various types of cancer. However, the role of ACS in cancer remains unknown. Here, we found that ACS enzyme activity is required for cancer cell survival. Namely, the ACS inhibitor Triacsin c induced massive apoptosis in glioma cells while this cell death was completely suppressed by overexpression of ACSL5, the Triacsin c-resistant ACS isozyme, but not by overexpression of a catalytically inactive ACSL5 mutant. ACS inhibition by Triacsin c markedly potentiated the Bax-induced intrinsic apoptotic pathway by promoting cytochrome c release and subsequent caspase activation. These effects were abrogated by ACSL5 overexpression. Correspondingly, ACS inhibition synergistically potentiated the glioma cell death induced by etoposide, a well-known activator of apoptosis. Furthermore, in a nude mouse xenograft model, Triacsin c at a non-toxic dose enhanced the antitumor efficacy of a low-dose chemotherapy with etoposide. These results indicate that ACS is an apoptosis suppressor and that ACS inhibition could be a rational strategy to amplify the antitumor effect of etoposide.

• Authors: Tetsuo Mashima, Shigeo Sato, Sachiko Okabe, Satoshi Miyata, Masaaki Matsuura, Yoshikazu Sugimoto, Takashi Tsuruo, Hiroyuki Seimiya
• Journal: Cancer science (Cancer Sci) Vol. 100 Issue 8 Pg. 1556-62 (Aug 2009) ISSN: 1349-7006 [Electronic] England
• PMID: 19459852 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents, Phytogenic
• Benzimidazoles
• Cytochrome c Group
• Fluorescent Dyes
• Indoles
• Isoenzymes
• Tetrazolium Salts
• Thiazoles
• Triazenes
• cytochrome c''
• 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium
• DAPI
• triacsin C
• Etoposide
• Caspases
• Coenzyme A Ligases
• long-chain-fatty-acid-CoA ligase
• bisbenzimide ethoxide trihydrochloride

Topics

• Animals
• Antineoplastic Agents, Phytogenic (pharmacology)
• Apoptosis (drug effects)
• Benzimidazoles (metabolism)
• Caspases (analysis)
• Catalysis
• Cell Line, Tumor
• Cell Survival (drug effects)
• Coenzyme A Ligases (antagonists & inhibitors)
• Cytochrome c Group (metabolism)
• Dose-Response Relationship, Drug
• Etoposide (pharmacology)
• Fluorescent Antibody Technique
• Fluorescent Dyes (metabolism)
• Glioma (genetics, pathology)
• Humans
• Indoles (metabolism)
• Injections, Subcutaneous
• Isoenzymes (antagonists & inhibitors)
• Mice
• Mice, Nude
• Neoplasm Transplantation
• Subcellular Fractions
• Tetrazolium Salts (metabolism)
• Thiazoles (metabolism)
• Triazenes (pharmacology)
• Tumor Burden
• Xenograft Model Antitumor Assays