Open AccessAcyl‐CoA synthetase as a cancer survival factor: its inhibition enhances the efficacy of etoposide
Author(s) -
Mashima Tetsuo,
Sato Shigeo,
Okabe Sachiko,
Miyata Satoshi,
Matsuura Masaaki,
Sugimoto Yoshikazu,
Tsuruo Takashi,
Seimiya Hiroyuki
Publication year - 2009
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/j.1349-7006.2009.01203.x
Subject(s) - etoposide , apoptosis , cancer research , programmed cell death , cancer cell , biology , glioma , cancer , pharmacology , chemistry , biochemistry , chemotherapy , genetics
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. ( Cancer Sci 2009)