TY - JOUR
T1 - Blocking signaling through the Gp130 receptor chain by interleukin-6 and oncostatin M inhibits PC-3 cell growth and sensitizes the tumor cells to etoposide and cisplatin-mediated cytotoxicity
AU - Borsellino, Nicolò
AU - Bonavida, Benjamin
AU - Ciliberto, Gennaro
AU - Toniatti, Carlo
AU - Travali, Salvatore
AU - D'Alessandro, Natale
PY - 1999/1/1
Y1 - 1999/1/1
N2 - BACKGROUND. The mechanisms of drug resistance associated with advanced, hormone-independent prostate carcinoma are poorly understood. The human prostate carcinoma PC-3 cell line, derived from a metastatic tumor and lacking androgen receptors, represents a useful model to investigate drug resistance. METHODS. The effects of oncostatin M (OM), antiinterleukin-6 (IL- 6) treatment, or interference with the gp130-mediated signaling on etoposide- or cisplatin-mediated cytotoxicity were investigated. RESULTS. Both endogenous and exogenous IL-6 and exogenous OM up-regulated cell growth and enhanced resistance of PC-S tumor cells to both etoposide and cisplatin. The influence of IL-6 is controlled by treating PC-3 tumor cells with anti-IL-6 neutralizing antibody and, more efficiently, by a mutated IL-6, Sant7. Sant7 has a high affinity binding to the IL-6 receptor-α (IL-6Rα) subunit, but does not bind to the signaling subunit gp130; therefore, it behaves as a receptor antagonist. Both IL-6- and OM-mediated effects are inhibited by the treatment of PC-3 with an antisense oligodeoxynucleotide against gp130, the protein kinase inhibitor genistein (GNS), or the monoterpene perillic acid (PA), a posttranslational inhibitor of p21 ras isoprenylation. CONCLUSIONS. These results demonstrate the protective roles in drug sensitivity of IL-6 and OM through signaling of the common chain gp130 and, most likely, a downstream ras-dependent pathway in PC-3 tumor cells. These findings suggest the potential clinical application of anticytokine therapy or interference with gp 130 signaling in the treatment of drug resistant prostate carcinoma.
AB - BACKGROUND. The mechanisms of drug resistance associated with advanced, hormone-independent prostate carcinoma are poorly understood. The human prostate carcinoma PC-3 cell line, derived from a metastatic tumor and lacking androgen receptors, represents a useful model to investigate drug resistance. METHODS. The effects of oncostatin M (OM), antiinterleukin-6 (IL- 6) treatment, or interference with the gp130-mediated signaling on etoposide- or cisplatin-mediated cytotoxicity were investigated. RESULTS. Both endogenous and exogenous IL-6 and exogenous OM up-regulated cell growth and enhanced resistance of PC-S tumor cells to both etoposide and cisplatin. The influence of IL-6 is controlled by treating PC-3 tumor cells with anti-IL-6 neutralizing antibody and, more efficiently, by a mutated IL-6, Sant7. Sant7 has a high affinity binding to the IL-6 receptor-α (IL-6Rα) subunit, but does not bind to the signaling subunit gp130; therefore, it behaves as a receptor antagonist. Both IL-6- and OM-mediated effects are inhibited by the treatment of PC-3 with an antisense oligodeoxynucleotide against gp130, the protein kinase inhibitor genistein (GNS), or the monoterpene perillic acid (PA), a posttranslational inhibitor of p21 ras isoprenylation. CONCLUSIONS. These results demonstrate the protective roles in drug sensitivity of IL-6 and OM through signaling of the common chain gp130 and, most likely, a downstream ras-dependent pathway in PC-3 tumor cells. These findings suggest the potential clinical application of anticytokine therapy or interference with gp 130 signaling in the treatment of drug resistant prostate carcinoma.
KW - Drug resistance
KW - Gp130
KW - Interleukin-6
KW - Oncostatin M
KW - Prostate cancer
KW - Resistance factors
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U2 - 10.1002/(SICI)1097-0142(19990101)85:1<134::AID-CNCR19>3.0.CO;2-C
DO - 10.1002/(SICI)1097-0142(19990101)85:1<134::AID-CNCR19>3.0.CO;2-C
M3 - Article
C2 - 9921985
AN - SCOPUS:0032922590
VL - 85
SP - 134
EP - 144
JO - Cancer
JF - Cancer
SN - 0008-543X
IS - 1
ER -