Combination of Carmustine and Selenite Inhibits EGFR Mediated Growth Signaling in Androgen-Independent Prostate Cancer Cells

Document Type

Article

Publication Date

12-1-2017

Publication Title

Journal of cellular biochemistry

Abstract

Although aberrant androgen receptor (AR) signaling is a central mechanism for castration resistant prostate cancer (CRPC) progression, AR-independent growth signaling is also present in CRPC. The current therapeutic options for patients with CRPC are limited and new drugs are desperately needed to eliminate these crucial growth signaling pathways. We have previously shown that combination of carmustine and selenite effectively induces apoptosis and growth inhibition by targeting AR and AR-variants in CRPC cells. High levels of EGFR expression present in the CRPC cells mediates the cell proliferation via AR-independent growth signaling mechanisms. Therefore, in this study, we investigated whether the combination of carmustine and selenite could inhibit EGFR mediated growth signaling and induce apoptosis in androgen independent-AR negative prostate cancer cells. EGF exposure dose and time dependently increased phospho-EGFR (Tyr845, Tyr1068, and Tyr1045), pAkt (Ser473), and pERK1/2 (Thr204/Tyr202) protein expression levels in AIPC cells. Combination of carmustine and selenite treatment markedly suppressed EGF-stimulated proliferation and survival of AIPC cells and effectively induced apoptosis. The ROS generated by the combination of carmustine and selenite exhibited a strong inhibition on EGF stimulated EGFR and its downstream signaling molecules such as Akt, NF-kB, ERK1/2, and Cyclin D1. Individual agent treatment showed only partial effect. Overall, our findings demonstrated that the combination of carmustine and selenite treatment dramatically inhibits EGFR signaling, proliferation, and induces apoptosis in AIPC cells, suggesting a potential candidate for the treatment of CRPC. The results of the study further suggest that the combination of carmustine and selenite treatment can overcome EGFR mediated AR-independent growth response in CRPC during anti-androgen therapy.

Medical Subject Headings

Apoptosis/drug effects; Carmustine/pharmacology; Cell Line; Tumor; Cell Proliferation/drug effects; ErbB Receptors/metabolism; Humans; MAP Kinase Signaling System/drug effects; Male; Mitogen-Activated Protein Kinase 1/metabolism; Mitogen-Activated Protein Kinase 3/metabolism; NF-kappa B/metabolism; Prostatic Neoplasms/mortality/pathology; Proto-Oncogene Proteins c-akt/metabolism; Selenious Acid/pharmacology; Androgen-independent prostate cancer; Akt; Carmustine; Castration resistant prostate cancer; Chemotherapy; Egfr; Erk1/2; Pc-3 cells; Selenite

PubMed ID

28430389

Volume

118

Issue

12

First Page

4331

Last Page

4340

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