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Open AccessArticle

Multifocal Signal Modulation Therapy by Celecoxib: A Strategy for Managing Castration-Resistant Prostate Cancer

1
Immunology, IRCCS Ospedale Policlinico San Martino, L.go R. Benzi 10, 16132 Genova, Italy
2
Academic Unit of Medical Oncology, IRCCS Ospedale Policlinico San Martino, L.go R. Benzi 10, 16132 Genova, Italy
3
Molecular Oncology & Angiogenesis, IRCCS Ospedale Policlinico San Martino, L.go R. Benzi 10, 16132 Genova, Italy
4
Department of Experimental Medicine (DIMES), University of Genova, Via L.B. Alberti, 16132 Genova, Italy
5
Department of Internal Medicine and Medical Specialties (DIMI), School of Medicine, University of Genoa, Via Balbi 5, 16126 Genova, Italy
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Int. J. Mol. Sci. 2019, 20(23), 6091; https://doi.org/10.3390/ijms20236091
Received: 22 October 2019 / Revised: 28 November 2019 / Accepted: 29 November 2019 / Published: 3 December 2019
(This article belongs to the Special Issue Cyclooxygenase and Cancer: Fundamental Molecular Investigations)
Background: Prostate cancer (PCa) is a significant health concern throughout the world. Standard therapy for advanced disease consists of anti-androgens, however, almost all prostate tumors become castration resistant (CRPC). Progression from androgen-sensitive PCa to CRPC is promoted by inflammatory signaling through cyclooxygenase-2 (COX-2) expression and ErbB family receptors/AKT activation, compensating androgen receptor inactivity. Methods: Making use of CRPC cell lines, we investigated the effects of the anti-inflammatory drug celecoxib. Biochemical data obtained using immunoblotting, enzyme-linked immunosorbent assay (ELISA), invasion, and xenografts were further integrated by bioinformatic analyses. Results: Celecoxib reduced cell growth and induced apoptosis through AKT blockade, cleavage of poly (ADP-ribose) polymerase-1 (PARP-1), and proteasomal degradation of the anti-apoptotic protein Mcl-1. Epidermal growth factor receptor (EGFR), ErbB2, and ErbB3 degradation, and heterogeneous nuclear ribonucleoprotein K (hnRNP K) downregulation, further amplified the inhibition of androgen signaling. Celecoxib reduced the invasive phenotype of CRPC cells by modulating NF-κB activity and reduced tumor growth in mice xenografts when administered in association with the anti-EGFR receptor antibody cetuximab. Bioinformatic analyses on human prostate cancer datasets support the relevance of these pathways in PCa progression. Conclusions: Signaling nodes at the intersection of pathways implicated in PCa progression are simultaneously modulated by celecoxib treatment. In combination therapies with cetuximab, celecoxib could represent a novel therapeutic strategy to curb signal transduction during CRPC progression. View Full-Text
Keywords: celecoxib; signaling; castration-resistant prostate cancer; ErbB family; inflammation; apoptosis celecoxib; signaling; castration-resistant prostate cancer; ErbB family; inflammation; apoptosis
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Benelli, R.; Barboro, P.; Costa, D.; Astigiano, S.; Barbieri, O.; Capaia, M.; Poggi, A.; Ferrari, N. Multifocal Signal Modulation Therapy by Celecoxib: A Strategy for Managing Castration-Resistant Prostate Cancer. Int. J. Mol. Sci. 2019, 20, 6091.

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