Regulation of HER expression and transactivation in human prostate cancer cells by a targeted cytotoxic bombesin analog (AN-215) and a bombesin antagonist (RC-3095)

Sandra Sotomayor, Laura Muñoz-Moreno, Marìa J. Carmena, Andrew V. Schally, Manuel Sànchez-Chapado, Juan C. Prieto, Ana M. Bajo

Research output: Contribution to journalArticle

12 Scopus citations

Abstract

Bombesin (BN) and gastrin-releasing peptide (GRP) have been shown to stimulate the growth of human prostate cancer in vivo and in vitro by mechanisms initiated by binding of the peptide to BN/GRP receptor (GRPR). GRPR is overexpressed in a variety of human cancers, including human prostatic carcinoma. This led us to evaluate the effectiveness of blocking GRPR and of chemotherapy targeted to GRPR in androgen-dependent (LNCaP) and androgen-independent (PC-3) prostate cancer cells, which exhibit different features of disease progression. Thus, we used a cytotoxic BN/GRP analog, AN-215, consisting of 2-pyrrolinodoxorubicin (AN-201) linked to BN-like carrier peptide, and a BN/GRP receptor antagonist, RC-3095. Semiquantitative RT-PCR and Western blotting revealed that mRNA and protein levels for GRPR increased in prostate cancer cells as compared with nonneoplastic RWPE-1 cells. Immunofluorocytochemistry and Western blot assays revealed that AN-215 was the most effective analog decreasing both the expression of epidermal growth factor receptor family members and the activation of epidermal growth factor receptor and HER-2, which are associated to a poor prognosis. Furthermore, analogs targeted to BN/GRP receptors, AN-215 and RC-3095, blocked the effect of BN on cell growth in RWPE-1, LNCaP and PC-3 cells. These findings shed light on the mechanisms of action of these analogs and support the view that the use of AN-215 and RC-3095 for blocking BN/GRP receptors for targeted therapy may be of benefit for treatment of advanced prostate cancer.

Original languageEnglish (US)
Pages (from-to)1813-1822
Number of pages10
JournalInternational Journal of Cancer
Volume127
Issue number8
DOIs
StatePublished - Oct 15 2010

Keywords

  • bombesin antagonist
  • cytotoxic bombesin analog
  • EGFR
  • HER-2
  • HER-2 transactivation
  • HER-3
  • prostate cancer

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Medicine(all)

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