Prostaglandin E(2) stimulates prostatic intraepithelial neoplasia cell growth through activation of the interleukin-6/GP130/STAT-3 signaling pathway.
Cyclooxygenase (COX)-2 expression and prostaglandin E(2) (PGE(2)) secretion are increased in prostatic intraepithelial neoplasia (PIN) and prostate cancer. PGE(2) biosynthesis by cyclooxygenase (COX)-2 plays a pivotal role in inflammation and carcinogenesis. One of the critical proinflammatory cytokines in the prostate is interleukin-6 (IL-6). We hypothesized that increased expression of COX-2, with resultant increased levels of PGE(2) in human PIN cells, activates the IL-6 signaling pathway. We demonstrate an autocrine upregulation of PGE(2) mediated by IL-6 in a human PIN cell line. We further demonstrate that PGE(2) stimulates soluble IL-6 receptor (sIL-6R) release, gp130 dimerization, Stat-3 protein phosphorylation, and DNA binding activity. These events, induced by PGE(2), lead to increased PIN cell growth. Treatment of PIN cells with a selective COX-2 inhibitor decreases cell growth. Finally, PGE(2)-stimulated PIN cell growth was abrogated by the addition of IL-6 neutralizing antibodies. These data provide mechanistic evidence that increased expression of COX-2/PGE(2) contributes to prostate cancer development and progression via activation of the IL-6 signaling pathway.
Liu
Xin-Hua
XH
Department of Medicine, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029, USA. liux01@doc.mssm.edu
Kirschenbaum
Alexander
A
Lu
Min
M
Yao
Shen
S
Klausner
Adam
A
Preston
Chad
C
Holland
James F
JF
Levine
Alice C
AC
D015703:Antigens, CD / Q000378:metabolism*; D002455:Cell Division; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D017077:Culture Media, Conditioned / Q000494:pharmacology; D050822:Cytokine Receptor gp130; D004268:DNA-Binding Proteins / Q000378:metabolism*; D019281:Dimerization; D015232:Dinoprostone / Q000096:biosynthesis*; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D015151:Immunoblotting; D015850:Interleukin-6 / Q000096:biosynthesis / Q000378:metabolism*; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism*; D010766:Phosphorylation; D011233:Precipitin Tests; D019048:Prostatic Intraepithelial Neoplasia / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000378:metabolism; D050796:STAT3 Transcription Factor; D015398:Signal Transduction; D013997:Time Factors; D015534:Trans-Activators / Q000378:metabolism*; D015854:Up-Regulation
D015703:Antigens, CD; D017077:Culture Media, Conditioned; D004268:DNA-Binding Proteins; C494199:IL6ST protein, human; D015850:Interleukin-6; D008562:Membrane Glycoproteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D015534:Trans-Activators; D050822:Cytokine Receptor gp130; D015232:Dinoprostone