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

Cancer. 1999 Jan 1;85(1):134-44.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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
  • Interleukin-6 / pharmacology
  • Interleukin-6 / physiology*
  • Male
  • Membrane Glycoproteins / drug effects*
  • Monoterpenes*
  • Oncostatin M
  • Peptides / pharmacology*
  • Prostatic Neoplasms / drug therapy
  • Signal Transduction / drug effects*
  • Terpenes / pharmacology
  • Tumor Cells, Cultured


  • 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