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Title: p38MAPK activation is involved in androgen-independent proliferation of human prostate cancer cells by regulating IL-6 secretion

Abstract

Increased levels of serum interleukin-6 (IL-6) are frequently observed in patients with advanced, hormone-refractory prostate cancer. However, the precise mechanism of IL-6 regulation is still largely unknown. Since prostate cancer gradually progresses to an androgen-independent state despite the stress caused by various therapeutic agents, we hypothesized the stress-activated protein kinases (SAPKs) involvement in androgen-independent growth or IL-6 secretion of prostate cancer cells. Using PC-3 and DU145 human prostate cancer cells, we analyzed the role of SAPKs in IL-6 mediated cell growth and found that the p38MAPK and JNK are involved in androgen-independent cancer cell growth. Furthermore, IL-6 secretion by PC-3 and DU145 cells was significantly suppressed by SAPKs inhibitor, especially by p38MAPK inhibitor SB203580, but not by JNK inhibitor SP600125 nor by MEK inhibitor, PD98059. These results raised the possibility that the IL-6 mediated androgen-independent proliferation of PC-3 and DU145 cells is regulated at least partly via SAPKs signaling pathway especially through p38MAPK activation.

Authors:
 [1];  [2];  [1];  [1];  [1]
  1. Division of Nephro-Urology, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki 852-8501 (Japan)
  2. Division of Nephro-Urology, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki 852-8501 (Japan). E-mail: tigawa@net.nagasaki-u.ac.jp
Publication Date:
OSTI Identifier:
20979799
Resource Type:
Journal Article
Resource Relation:
Journal Name: Biochemical and Biophysical Research Communications; Journal Volume: 353; Journal Issue: 3; Other Information: DOI: 10.1016/j.bbrc.2006.12.077; PII: S0006-291X(06)02756-2; Copyright (c) 2006 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ANDROGENS; BIOLOGICAL STRESS; CELL PROLIFERATION; DRUGS; NEOPLASMS; PATIENTS; PHOSPHOTRANSFERASES; PROSTATE; SECRETION

Citation Formats

Shida, Yohei, Igawa, Tsukasa, Hakariya, Tomoaki, Sakai, Hideki, and Kanetake, Hiroshi. p38MAPK activation is involved in androgen-independent proliferation of human prostate cancer cells by regulating IL-6 secretion. United States: N. p., 2007. Web. doi:10.1016/j.bbrc.2006.12.077.
Shida, Yohei, Igawa, Tsukasa, Hakariya, Tomoaki, Sakai, Hideki, & Kanetake, Hiroshi. p38MAPK activation is involved in androgen-independent proliferation of human prostate cancer cells by regulating IL-6 secretion. United States. doi:10.1016/j.bbrc.2006.12.077.
Shida, Yohei, Igawa, Tsukasa, Hakariya, Tomoaki, Sakai, Hideki, and Kanetake, Hiroshi. Fri . "p38MAPK activation is involved in androgen-independent proliferation of human prostate cancer cells by regulating IL-6 secretion". United States. doi:10.1016/j.bbrc.2006.12.077.
@article{osti_20979799,
title = {p38MAPK activation is involved in androgen-independent proliferation of human prostate cancer cells by regulating IL-6 secretion},
author = {Shida, Yohei and Igawa, Tsukasa and Hakariya, Tomoaki and Sakai, Hideki and Kanetake, Hiroshi},
abstractNote = {Increased levels of serum interleukin-6 (IL-6) are frequently observed in patients with advanced, hormone-refractory prostate cancer. However, the precise mechanism of IL-6 regulation is still largely unknown. Since prostate cancer gradually progresses to an androgen-independent state despite the stress caused by various therapeutic agents, we hypothesized the stress-activated protein kinases (SAPKs) involvement in androgen-independent growth or IL-6 secretion of prostate cancer cells. Using PC-3 and DU145 human prostate cancer cells, we analyzed the role of SAPKs in IL-6 mediated cell growth and found that the p38MAPK and JNK are involved in androgen-independent cancer cell growth. Furthermore, IL-6 secretion by PC-3 and DU145 cells was significantly suppressed by SAPKs inhibitor, especially by p38MAPK inhibitor SB203580, but not by JNK inhibitor SP600125 nor by MEK inhibitor, PD98059. These results raised the possibility that the IL-6 mediated androgen-independent proliferation of PC-3 and DU145 cells is regulated at least partly via SAPKs signaling pathway especially through p38MAPK activation.},
doi = {10.1016/j.bbrc.2006.12.077},
journal = {Biochemical and Biophysical Research Communications},
number = 3,
volume = 353,
place = {United States},
year = {Fri Feb 16 00:00:00 EST 2007},
month = {Fri Feb 16 00:00:00 EST 2007}
}
  • The androgen receptor (AR) regulates growth and progression of androgen-dependent as well as androgen-independent prostate cancer cells. Peroxisome proliferator-activated receptor gamma (PPAR{gamma}) agonists have been reported to reduce AR activation in androgen-dependent LNCaP prostate cancer cells. To determine whether PPAR{gamma} ligands are equally effective at inhibiting AR activity in androgen-independent prostate cancer, we examined the effect of the PPAR{gamma} ligands ciglitazone and rosiglitazone on C4-2 cells, an androgen- independent derivative of the LNCaP cell line. Luciferase-based reporter assays and Western blot analysis demonstrated that PPAR{gamma} ligand reduced dihydrotestosterone (DHT)-induced increases in AR activity in LNCaP cells. However, in C4-2 cells,more » these compounds increased DHT-induced AR driven luciferase activity. In addition, ciglitazone did not significantly alter DHT-mediated increases in prostate specific antigen (PSA) protein or mRNA levels within C4-2 cells. siRNA-based experiments demonstrated that the ciglitazone-induced regulation of AR activity observed in C4-2 cells was dependent on the presence of PPAR{gamma}. Furthermore, overexpression of the AR corepressor cyclin D1 inhibited the ability of ciglitazone to induce AR luciferase activity in C4-2 cells. Thus, our data suggest that both PPAR{gamma} and cyclin D1 levels influence the ability of ciglitazone to differentially regulate AR signaling in androgen-independent C4-2 prostate cancer cells.« less
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