Neoplasia: An International Journal for Oncology Research (Jan 2004)

15-Lipoxygenase-1 Expression Upregulates and Activates Insulin-Like Growth Factor-1 Receptor in Prostate Cancer Cells

  • Uddhav P. Kelavkar,
  • Cynthia Cohen

DOI
https://doi.org/10.1016/S1476-5586(04)80052-6
Journal volume & issue
Vol. 6, no. 1
pp. 41 – 52

Abstract

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We previously discovered that a fat-metabolizing enzyme, 15-lipoxygenase-1 (15-LO-1), is high in human prostate cancer (PCa) and correlates with disease progression. The biologic link between the aberrant 15-LO-1/linoleic acid (LA) metabolism and fat (which is a rich source of growth factors) in PCa is unknown. Therefore, we tested the hypothesis that the metabolic product of the polyunsaturated fatty acid LA (i.e., 13-Shydroxyoctadecadienoic acid or 13-(S)-NODE) affects the proliferation status of PCa cells through one or more growth factors. We used parental prostate cancer cell line-3 (PC-3) and engineered PC-3 cell lines [PC3Zeo (mock-transfected), PC3-15LOS (15-LO-1-overexpressing), and PC3-15LOAS (15-LO-1-blocked)] to test our hypothesis. Of the growth factors examined, only insulin-like growth factor-1 (IGF-1) exhibited a two-fold to three-fold increase in growth response on PC315LOS cells compared to PC3-Zeo (control) cell line (P < .01). Insulin-like growth factor-1 receptor (IGF-1 R) immunohistochemical analyses of human normal and adenocarcinoma prostate tissues, as well as levels in tumors derived from nude mice injected with PC-3 cells, demonstrated that elevated IGF-1 R expression correlated with 15-LO-1 levels. Radioligand binding assays demonstrated two-fold higher IGF-1 binding sites in PC3-15LOS cells (P < .05 vs PC3-Zeo cells). IGF-1 R promoter reporter assay and affinity-purified IGF-1 R receptor levels demonstrated a four-fold higher activity in PC3-15LOS cells (P < .01 vs PC3-Zeo cells). IGF-1 R promoter activation is 13-(S)-NODE-dependent. IGF-1 R blockade with a dominant-negative adenovirus caused significant growth inhibition in PC-3 cells (P < .0001; PC3-15LOAS versus PC3-15LOS cells), as well as affected the IGF-1-stimulated mitogen-activated protein (MAP) kinase (Erki/2) and Akt activation levels. Our study suggests that overexpression of 15LO-1 in PCa contributes to the cancer progression by regulating IGF-1 R expression and activation.

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