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

Nicolò Borsellino, Benjamin Bonavida, Gennaro Ciliberto, Carlo Toniatti, Salvatore Travali, Natale D'Alessandro

Research output: Contribution to journalArticle

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-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.

Original languageEnglish
Pages (from-to)134-144
Number of pages11
JournalCancer
Volume85
Issue number1
DOIs
Publication statusPublished - Jan 1 1999

Keywords

  • Drug resistance
  • Gp130
  • Interleukin-6
  • Oncostatin M
  • Prostate cancer
  • Resistance factors

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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