Acyl-CoA synthetase as a cancer survival factor

Its inhibition enhances the efficacy of etoposide

Tetsuo Mashima, Shigeo Sato, Sachiko Okabe, Satoshi Miyata, Masaaki Matsuura, Yoshikazu Sugimoto, Takashi Tsuruo, Hiroyuki Seimiya

Research output: Contribution to journalArticle

35 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1556-1562
Number of pages7
JournalCancer Science
Volume100
Issue number8
DOIs
Publication statusPublished - 2009

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Coenzyme A Ligases
Etoposide
Neoplasms
Apoptosis
Glioma
Cell Death
Acyl Coenzyme A
Caspases
Cytochromes c
Lipid Metabolism
Heterografts
Nude Mice
Isoenzymes
Cell Survival
Fatty Acids
Drug Therapy

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Acyl-CoA synthetase as a cancer survival factor : Its inhibition enhances the efficacy of etoposide. / Mashima, Tetsuo; Sato, Shigeo; Okabe, Sachiko; Miyata, Satoshi; Matsuura, Masaaki; Sugimoto, Yoshikazu; Tsuruo, Takashi; Seimiya, Hiroyuki.

In: Cancer Science, Vol. 100, No. 8, 2009, p. 1556-1562.

Research output: Contribution to journalArticle

Mashima, T, Sato, S, Okabe, S, Miyata, S, Matsuura, M, Sugimoto, Y, Tsuruo, T & Seimiya, H 2009, 'Acyl-CoA synthetase as a cancer survival factor: Its inhibition enhances the efficacy of etoposide', Cancer Science, vol. 100, no. 8, pp. 1556-1562. https://doi.org/10.1111/j.1349-7006.2009.01203.x
Mashima, Tetsuo ; Sato, Shigeo ; Okabe, Sachiko ; Miyata, Satoshi ; Matsuura, Masaaki ; Sugimoto, Yoshikazu ; Tsuruo, Takashi ; Seimiya, Hiroyuki. / Acyl-CoA synthetase as a cancer survival factor : Its inhibition enhances the efficacy of etoposide. In: Cancer Science. 2009 ; Vol. 100, No. 8. pp. 1556-1562.
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