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The acyl‐CoA synthetase ACSVL3 maintains the malignant phenotype of human gliomas
Author(s) -
Watkins Paul A.,
Pei Zhengtong,
Sun Peng,
Huang Ping,
Lal Bachchu,
Laterra John
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.23.1_supplement.520.10
Subject(s) - glioma , gene knockdown , protein kinase b , receptor tyrosine kinase , diacylglycerol kinase , phosphatidylinositol , cancer research , chemistry , pi3k/akt/mtor pathway , kinase , signal transduction , biology , biochemistry , microbiology and biotechnology , apoptosis , protein kinase c
The contribution of lipid metabolic pathways to malignancies is poorly understood. Expression of the fatty acyl‐CoA synthetase, ACSVL3, was markedly elevated in malignant gliomas but nearly undetectable in normal glia. ACSVL3 knockdown (KD) in cultured glioma cells using RNA interference significantly reduced both their in vitro malignant growth properties and in vivo tumorigenicity. Subcutaneous xenografts produced from ACSVL3 KD cells grew ~60% slower than control tumors and intracranial KD xenografts were ~85% smaller than controls. KD glioma cells had decreased capacity to activate fatty acids containing 16‐24 carbons. Incorporation of labeled palmitate (C16:0) into signaling lipids such as diacylglycerol and phosphatidylinositol, but not bulk membrane lipids, was reduced in KD cells. ACSVL3 expression was induced by activating oncogenic receptor tyrosine kinases (RTK) c‐Met and EGFR. ACSVL3 KD disrupted Akt responses to RTK activation, with a transient loss of both total and phosphorylated Akt via a caspase‐dependent mechanism. Our results show that ACSVL3 maintains oncogenic properties of malignant glioma cells via a mechanism that involves, in part, the regulation of Akt function and synthesis of signaling lipids. Targeting ACSVL3 could be therapeutically beneficial in malignant glioma and perhaps other cancers. Supported by NIH grants NS37355 (PAW) and NS43987 (JL).