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Downregulation of vascular endothelial growth factor and induction of tumor dormancy by 15‐lipoxygenase‐2 in prostate cancer
Author(s) -
Tang Yong,
Wang ManTzu,
Chen Yakun,
Yang Dianer,
Che Mingxin,
Honn Kenneth V.,
Akers Gregory D.,
Johnson Stephen R.,
Nie Daotai
Publication year - 2009
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.24118
Subject(s) - prostate cancer , du145 , cancer research , cancer , prostate , arachidonic acid , vascular endothelial growth factor , cancer cell , biology , medicine , lncap , biochemistry , enzyme , vegf receptors
The enzyme 15‐lipoxygenase‐2 (15‐LOX‐2) utilizes arachidonic acid, a polyunsaturated fatty acid, to synthesize 15( S )‐hydroxyeicosatetraenoic acid. Abundantly expressed in normal prostate epithelium but frequently suppressed in the cancerous tissues, 15‐LOX‐2 has been suggested as a functional suppressor of prostate cancer, but the mechanism(s) involved remains unknown. To study the functional role of 15‐LOX‐2 in prostate cancer, we expressed 15‐LOX‐2 as a fusion protein with GFP in DU145 and PC‐3 cells and found that 15‐LOX‐2 increased cell cycle arrest at G0/G1 phase. When injected into athymic nu/nu mice, prostate cancer cells with 15‐LOX‐2 expression could still form palpable tumors without significant changes in tumorigenicity. But, the tumors with 15‐LOX‐2 expression grew significantly slower than those derived from vector controls and were kept dormant for a long period of time. Histological evaluation revealed an increase in cell death in tumors derived from prostate cancer cells with 15‐LOX‐2 expression, while in vitro cell culture conditions, no such increase in apoptosis was observed. Further studies found that the expression of vascular endothelial growth factor A (VEGF‐A) was significantly reduced in prostate cancer cells with 15‐LOX‐2 expression restored. Our studies suggest that 15‐LOX‐2 suppresses VEGF gene expression and sustains tumor dormancy in prostate cancer. Loss of 15‐LOX‐2 functionalities, therefore, represents a key step for prostate cancer cells to exit from dormancy and embark on malignant progression in vivo . © 2008 Wiley‐Liss, Inc.