Differential expression of cyclooxygenase-2 and its regulation by tumor necrosis factor-alpha in normal and malignant prostate cells.
Cyclooxygenase (COX)-2 expression is elevated in some malignancies; however, information is scarce regarding COX-2 contributions to the development of prostate cancer and its regulation by inflammatory cytokines. The present study compared and contrasted the expression levels and subcellular distribution patterns of COX-1 and COX-2 in normal prostate [prostate epithelial cell (PrEC), prostate smooth muscle (PrSM), and prostate stromal (PrSt)] primary cell cultures and prostatic carcinoma cell lines (PC-3, LNCaP, and DU145). The basal COX-2 mRNA and protein levels were high in normal PrEC and low in tumor cells, unlike many other normal cells and tumor cells. Because COX-2 levels were low in prostate smooth muscle cells, prostate stromal cells, and tumor cells, we also examined whether COX-1 and COX-2 gene expression was elevated in response to tumor necrosis factor-alpha (TNF-alpha), a strong inducer of COX-2 expression. Northern blot analysis and reverse transcription-PCR demonstrated different patterns and kinetics of expression for COX-1 and COX-2 among normal cells and tumor cells in response to TNF-alpha. In particular, COX-2 protein levels increased, and the subcellular distribution formed a distinct perinuclear ring in the normal cells at 4 h after TNF-alpha exposure. The COX-2 protein levels also increased in cancer cells, but the subcellular distribution was less organized; COX-2 protein appeared diffuse in some cells and accumulated as focal deposits in the cytoplasm of other cells. TNF-alpha induction of COX-2 and prostaglandin E2 correlated inversely with induction of apoptosis. We conclude that COX-2 expression may be important to PrEC cell function. Although it is low in stromal and tumor cells, COX-2 expression is induced by TNF-alpha in these cells, and this responsiveness may play an important role in prostate cancer progression.
Subbarayan
V
V
Department of Clinical Cancer Prevention, The University of Texas M. D. Anderson Cancer Center, Houston 77030, USA.
Sabichi
A L
AL
Llansa
N
N
Lippman
S M
SM
Menter
D G
DG
D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D015152:Blotting, Northern; D002478:Cells, Cultured; D051546:Cyclooxygenase 2; D015232:Dinoprostone / Q000096:biosynthesis; D004790:Enzyme Induction / Q000187:drug effects; D005455:Fluorescent Antibody Technique; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007527:Isoenzymes / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D011467:Prostate / Q000187:drug effects / Q000201:enzymology*; D011471:Prostatic Neoplasms / Q000201:enzymology*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013347:Subcellular Fractions / Q000187:drug effects / Q000201:enzymology; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects
D007527:Isoenzymes; D008565:Membrane Proteins; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone