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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)
Author(s) -
Sotomayor Sandra,
MuñozMoreno Laura,
Carmena María J.,
Schally Andrew V.,
SánchezChapado Manuel,
Prieto Juan C.,
Bajo Ana M.
Publication year - 2010
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.25192
Subject(s) - lncap , bombesin , gastrin releasing peptide , prostate cancer , cancer research , transactivation , receptor , du145 , cytotoxic t cell , endocrinology , medicine , biology , cancer , in vitro , gene expression , biochemistry , neuropeptide , gene
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.