期刊
INTERNATIONAL JOURNAL OF CANCER
卷 124, 期 7, 页码 1545-1551出版社
WILEY
DOI: 10.1002/ijc.24118
关键词
tumor dormancy; angiogenesis; lipoxygenase; prostate cancer; VEGF
类别
资金
- National Institute of Health [R01CA029997, R01CA131445]
- United States Department of Defense Prostate Cancer Research Program New Investigator Award [W81XWH-04-1-0143]
- Illinois Department of Public Health Prostate Cancer Research Program
- Southern Illinois University School of Medicine and SimmonsCooper Cancer Institute
The enzyme 15-lipoxygenase-2 (15-LOX-2) utilizes arachidonic acid, a polyunsaturated fatty acid, to synthesize 15(S)-hydroxycosatetraenoic 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 its vivo. (C) 2008 Wiley-Liss, Inc.
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