PMID- 28450158 OWN - NLM STAT- MEDLINE DCOM- 20170825 LR - 20181202 IS - 1872-7980 (Electronic) IS - 0304-3835 (Linking) VI - 400 DP - 2017 Aug 1 TI - The ErbB family and androgen receptor signaling are targets of Celecoxib in prostate cancer. PG - 9-17 LID - S0304-3835(17)30285-9 [pii] LID - 10.1016/j.canlet.2017.04.025 [doi] AB - Inflammation plays a central role in prostate cancer (PCa) development through significant crosstalk between the COX-2-ErbB family receptor network and androgen receptor (AR)-EGFR signaling pathways. The purpose of this work was to determine the ability of the COX-2 inhibitor Celecoxib to modulate the EGFR-AR signaling pathway in androgen-dependent PCa cells and to provide a rationale for its beneficial use in chemopreventive strategies. Functional studies of Celecoxib activity were performed on LNCaP prostate cancer cells. Western blotting, gene expression analysis, dual-luciferase reporter assay and ELISA were applied to assess the Celecoxib mechanisms of action. We found that Celecoxib, through EGF and amphiregulin (AREG) induction, caused EGFR and ErbB2 activation and consequent degradation associated with the inhibition of androgenic signaling. By upregulating the E3 ubiquitin ligase Nrdp1, Celecoxib also efficiently downregulated ErbB3, which is strongly implicated in castration-resistant prostate cancer. Lastly, Celecoxib directly regulated AR transcription and translation independent of ErbB activation by downregulating the RNA binding protein heterogeneous nuclear ribonucleoprotein K (hnRNP K). The simultaneous suppression of ErbB kinases and androgen signaling by Celecoxib represents a novel strategy to interrupt the vicious cycle of AR/ErbB cross-talk with the primary purpose of undermining their resilient signaling in prostate cancer progression. Our data provide important premises for the chemopreventive use of Celecoxib in the clinical management of prostate cancer. CI - Copyright (c) 2017 Elsevier B.V. All rights reserved. FAU - Brizzolara, Antonella AU - Brizzolara A AD - Molecular Oncology & Angiogenesis, IRCCS AOU San Martino, IST Istituto Nazionale per la Ricerca sul Cancro, Largo Rosanna Benzi 10, 16132 Genoa, Italy. FAU - Benelli, Roberto AU - Benelli R AD - Immunology, IRCCS AOU San Martino, IST Istituto Nazionale per la Ricerca sul Cancro, Largo Rosanna Benzi 10, 16132 Genoa, Italy. FAU - Vene, Roberta AU - Vene R AD - Molecular Oncology & Angiogenesis, IRCCS AOU San Martino, IST Istituto Nazionale per la Ricerca sul Cancro, Largo Rosanna Benzi 10, 16132 Genoa, Italy. FAU - Barboro, Paola AU - Barboro P AD - Academic Unit of Medical Oncology, IRCCS AOU San Martino, IST Istituto Nazionale per la Ricerca sul Cancro, Largo Rosanna Benzi 10, 16132 Genoa, Italy. FAU - Poggi, Alessandro AU - Poggi A AD - Molecular Oncology & Angiogenesis, IRCCS AOU San Martino, IST Istituto Nazionale per la Ricerca sul Cancro, Largo Rosanna Benzi 10, 16132 Genoa, Italy. FAU - Tosetti, Francesca AU - Tosetti F AD - Molecular Oncology & Angiogenesis, IRCCS AOU San Martino, IST Istituto Nazionale per la Ricerca sul Cancro, Largo Rosanna Benzi 10, 16132 Genoa, Italy. FAU - Ferrari, Nicoletta AU - Ferrari N AD - Molecular Oncology & Angiogenesis, IRCCS AOU San Martino, IST Istituto Nazionale per la Ricerca sul Cancro, Largo Rosanna Benzi 10, 16132 Genoa, Italy. Electronic address: nicoletta.ferrari@hsanmartino.it. LA - eng PT - Journal Article DEP - 20170425 PL - Ireland TA - Cancer Lett JT - Cancer letters JID - 7600053 RN - 0 (AR protein, human) RN - 0 (AREG protein, human) RN - 0 (Amphiregulin) RN - 0 (Androgen Antagonists) RN - 0 (Antineoplastic Agents) RN - 0 (Heterogeneous-Nuclear Ribonucleoprotein K) RN - 0 (Protein Kinase Inhibitors) RN - 0 (Receptors, Androgen) RN - 0 (Ribonucleoproteins) RN - 146410-60-8 (HNRNPK protein, human) RN - 62229-50-9 (Epidermal Growth Factor) RN - EC 2.3.2.27 (RNF41 protein, human) RN - EC 2.3.2.27 (Ubiquitin-Protein Ligases) RN - EC 2.7.10.1 (EGFR protein, human) RN - EC 2.7.10.1 (ERBB2 protein, human) RN - EC 2.7.10.1 (ERBB3 protein, human) RN - EC 2.7.10.1 (ErbB Receptors) RN - EC 2.7.10.1 (Receptor, ErbB-2) RN - EC 2.7.10.1 (Receptor, ErbB-3) RN - JCX84Q7J1L (Celecoxib) SB - IM MH - Amphiregulin/genetics/metabolism MH - Androgen Antagonists/*pharmacology MH - Antineoplastic Agents/*pharmacology MH - Apoptosis/drug effects MH - Celecoxib/*pharmacology MH - Dose-Response Relationship, Drug MH - Epidermal Growth Factor/genetics/metabolism MH - ErbB Receptors/*antagonists & inhibitors/genetics/metabolism MH - Gene Expression Regulation, Neoplastic MH - Heterogeneous-Nuclear Ribonucleoprotein K MH - Humans MH - Male MH - Prostatic Neoplasms/*drug therapy/enzymology/genetics/pathology MH - Protein Kinase Inhibitors/*pharmacology MH - Proteolysis MH - Receptor, ErbB-2/*antagonists & inhibitors/metabolism MH - Receptor, ErbB-3/*antagonists & inhibitors/metabolism MH - Receptors, Androgen/*drug effects/genetics/metabolism MH - Ribonucleoproteins/genetics/metabolism MH - Signal Transduction/*drug effects MH - Time Factors MH - Transcription, Genetic MH - Ubiquitin-Protein Ligases/metabolism OTO - NOTNLM OT - Androgen receptor OT - Celecoxib OT - Chemoprevention OT - ErbB receptors OT - Prostate cancer OT - hnRNP K EDAT- 2017/04/30 06:00 MHDA- 2017/08/26 06:00 CRDT- 2017/04/29 06:00 PHST- 2017/01/16 00:00 [received] PHST- 2017/04/06 00:00 [revised] PHST- 2017/04/14 00:00 [accepted] PHST- 2017/04/30 06:00 [pubmed] PHST- 2017/08/26 06:00 [medline] PHST- 2017/04/29 06:00 [entrez] AID - S0304-3835(17)30285-9 [pii] AID - 10.1016/j.canlet.2017.04.025 [doi] PST - ppublish SO - Cancer Lett. 2017 Aug 1;400:9-17. doi: 10.1016/j.canlet.2017.04.025. Epub 2017 Apr 25.