Cloning, Expression, and Chromosomal Localization of Human Long-Chain Fatty Acid-CoA Ligase 4 (FACL4)

Cao, Yang; Traer, Elie; Zimmerman, Guy A.; McIntyre, Thomas M.; Prescott, Stephen M.

doi:10.1006/geno.1998.5268

Cited by 114 publications

(96 citation statements)

References 10 publications

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“…We previously cloned the human isoform 4 of the fatty acid CoAligase gene. It encodes an enzyme that highly prefers AA as substrate and that converts it into arachidonoyl CoA ester (20). Because FACL4 and COX-2 both use AA as substrate and COX-2 was shown to be induced in colon cancer (8, 9), we asked whether FACL4 is also up-regulated in colon adenocarcinomas.…”

Section: Resultsmentioning

confidence: 99%

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Intracellular unesterified arachidonic acid signals apoptosis

Cao

Pearman

Zimmerman

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

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Cyclooxygenase-2 (COX-2) is up-regulated in many cancers and is a rate-limiting step in colon carcinogenesis. Nonsteroidal antiinflammatory drugs, which inhibit COX-2, prevent colon cancer and cause apoptosis. The mechanism for this response is not clear, but it might result from an accumulation of the substrate, arachidonic acid, an absence of a prostaglandin product, or diversion of the substrate into another pathway. We found that colon adenocarcinomas overexpress another arachidonic acid-utilizing enzyme, fatty acid-CoA ligase (FACL) 4, in addition to COX-2. Exogenous arachidonic acid caused apoptosis in colon cancer and other cell lines, as did triacsin C, a FACL inhibitor. In addition, indomethacin and sulindac significantly enhanced the apoptosis-inducing effect of triacsin C. These findings suggested that unesterified arachidonic acid in cells is a signal for induction of apoptosis. To test this hypothesis, we engineered cells with inducible overexpression of COX-2 and FACL4 as ''sinks'' for unesterified arachidonic acid. Activation of the enzymatic sinks blocked apoptosis, and the reduction of cell death was inversely correlated with the cellular level of arachidonic acid. Inhibition of the COX-2 component by nonsteroidal antiinflammatory drugs restored the apoptotic response. Cell death caused by exposure to tumor necrosis factor ␣ or to calcium ionophore also was prevented by removal of unesterified arachidonic acid. We conclude that the cellular level of unesterified arachidonic acid is a general mechanism by which apoptosis is regulated and that COX-2 and FACL4 promote carcinogenesis by lowering this level.

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Section: Resultsmentioning

confidence: 99%

“…In this study, we found that fatty acid-CoA ligase (FACL) 4, which highly prefers AA as substrate (20), also was up-regulated in colon adenocarcinomas. This suggests that the alterations of AA metabolic pathways lower the level of unesterified AA and thereby prevent apoptosis.…”

mentioning

confidence: 76%

Intracellular unesterified arachidonic acid signals apoptosis

Cao

Pearman

Zimmerman

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

381

291

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“…There are five FACL isoenzymes present in human tissues [4,5] . Of these, FACL4 could highly express in human steroidogenic tissues, such as placenta, brain, testis, ovary, spleen, and adrenal cortex, whereas it is less expressed in the gastrointestinal system, including liver [6] . FACL4 is highly elevated in colon adenocarcinoma and plays an important role in colon carcinogenesis [7] .…”

Section: Introductionmentioning

confidence: 99%

Involvement of fatty acid-CoA ligase 4 in hepatocellular carcinoma growth: Roles of cyclic AMP and p38 mitogen-activated protein kinase

Liang

Chu³

et al. 2005

WJG

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AIM: Fatty acid-CoA ligase 4 (FACL4) is an arachidonatepreferring enzyme which has been shown to be up-regulated in human colon cancer tissues and implicated in the colon tumorigenesis. The purpose of this study was to investigate the role of FACL4 in the human hepatocellular carcinoma (HCC) tumorigenesis and the specific signal pathways involved in this process. METHODS:We investigated the expression and regulation of FACL4 in HCC, adjacent non-tumorous liver tissues, and cell lines. RESULTS:In HCC patients, we demonstrated that FACL4 gene expression was markedly elevated in the cancerous tissues than in the adjacent non-cancerous liver tissues. In addition, several human hepatoma cell lines, including Hep3B and HepG2, expressed high levels of FACL4. Stable overex-pression of FACL4 knockdown plasmids (small interfering RNA, siRNA) to Hep3B cells significantly decreased FACL4 expression and subsequently limited the cell proliferation. Treatment of Hep3B cells with 8-bromo-cAMP and SB203508 (p38 MAPK inhibitor) significantly suppressed the FACL4 expression.CONCLUSION: FACL4 is involved in the HCC tumorigenesis and both cAMP and p38 MAPK pathways are associated with the regulation of FACL4 in HCC.

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“…The FACL4 isoform, located in mitochondrial associated membrane and on the peroxisomal membrane, prefers AA and EPA as substrate. It is mainly expressed in the steroidogenic tissues but also in neuronal and smooth muscle cells (Kang et al 1997;Cao et al 1998;Coleman et al 2002;Askari et al 2007). The FACL4 gene is mapped to the long arm of human chromosome X, region q23 (Cao et al 1998).…”

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confidence: 99%

“…It is mainly expressed in the steroidogenic tissues but also in neuronal and smooth muscle cells (Kang et al 1997;Cao et al 1998;Coleman et al 2002;Askari et al 2007). The FACL4 gene is mapped to the long arm of human chromosome X, region q23 (Cao et al 1998). Mutations of FACL4 gene was found to be connected with X-linked mental retardation (Piccini et al 1998).…”

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confidence: 99%