Journal Article

Fatty acid regulates gene expression and growth of human prostate cancer PC-3 cells

Millie Hughes-Fulford, Yunfei Chen and Raymond R. Tjandrawinata

in Carcinogenesis

Volume 22, issue 5, pages 701-707
Published in print May 2001 | ISSN: 0143-3334
Published online May 2001 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/22.5.701
Fatty acid regulates gene expression and growth of human prostate cancer PC-3 cells

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It has been proposed that the ω-6 fatty acids increase the rate of tumor growth. Here we test that hypothesis in the PC-3 human prostate tumor. We found that the essential fatty acids, linoleic acid (LA) and arachidonic acid (AA), and the AA metabolite PGE2 stimulate tumor growth while oleic acid (OA) and the ω-3 fatty acid, eicosapentaenoic acid (EPA) inhibited growth. In examining the role of AA in growth response, we extended our studies to analyze changes in early gene expression induced by AA. We demonstrate that c-fos expression is increased within minutes of addition in a dose-dependent manner. Moreover, the immediate early gene cox-2 is also increased in the presence of AA in a dose-dependent manner, while the constitutive cox-1 message was not increased. Three hours after exposure to AA, the synthesis of PGE2 via COX-2 was also increased. Previous studies have demonstrated that AA was primarily delivered by low density lipoprotein (LDL) via its receptor (LDLr). Since it is known that hepatomas, acute myelogenous leukemia and colorectal tumors lack normal cholesterol feedback, we examined the role of the LDLr in growth regulation of the PC-3 prostate cancer cells. Analysis of ldlr mRNA expression and LDLr function demonstrated that human PC-3 prostate cancer cells lack normal feedback regulation. While exogenous LDL caused a significant stimulation of cell growth and PGE2 synthesis, no change was seen in regulation of the LDLr by LDL. Taken together, these data show that normal cholesterol feedback of ldlr message and protein is lost in prostate cancer. These data suggest that unregulated over-expression of LDLr in tumor cells would permit increased availability of AA, which induces immediate early genes c-fos and cox-2 within minutes of uptake.

Keywords: AA, arachidonic acid; COX, cyclooxygenase; dmPGE2, 16,16-dimethyl PGE2; EFA, essential fatty acids; FA, fatty acid; FCS, fetal calf serum; LDL, low density lipoprotein; LDLr, low density lipoprotein receptor; LOX, lipoxygenase; LPDS, lipoprotein-deficient serum; LTs, leukotrienes; PGs, prostaglandins; PLA2, phospholipase A2; PPARs, peroxisome proliferator-activated receptors; PPRE, peroxisome proliferator receptor element; PUFA, polyunsaturated fatty acids; TXs, thromboxanes.

Journal Article.  5175 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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