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.

Abstract

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-3 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-alpha (IL-6Ralpha) 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 p21ras 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 gp130 signaling in the treatment of drug resistant prostate carcinoma.

• Authors: N Borsellino, B Bonavida, G Ciliberto, C Toniatti, S Travali, N D'Alessandro
• Journal: Cancer (Cancer) Vol. 85 Issue 1 Pg. 134-44 (Jan 01 1999) ISSN: 0008-543X [Print] United States
• PMID: 9921985 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antigens, CD
• Antineoplastic Agents
• Antineoplastic Agents, Phytogenic
• Cyclohexenes
• IL6ST protein, human
• Interleukin-6
• Membrane Glycoproteins
• Monoterpenes
• OSM protein, human
• Peptides
• Terpenes
• Oncostatin M
• Cytokine Receptor gp130
• Etoposide
• perillic acid
• Genistein
• Cisplatin

Topics

• Antigens, CD (drug effects)
• Antineoplastic Agents (pharmacology)
• Antineoplastic Agents, Phytogenic (pharmacology)
• Cisplatin (pharmacology)
• Cyclohexenes
• Cytokine Receptor gp130
• Drug Resistance, Neoplasm (physiology)
• Etoposide (pharmacology)
• Genistein (pharmacology)
• Humans
• Interleukin-6 (immunology, pharmacology, physiology)
• Male
• Membrane Glycoproteins (drug effects)
• Monoterpenes
• Oncostatin M
• Peptides (pharmacology)
• Prostatic Neoplasms (drug therapy)
• Signal Transduction (drug effects)
• Terpenes (pharmacology)
• Tumor Cells, Cultured