Implication of NPM1 phosphorylation and preclinical evaluation of the nucleoprotein antagonist N6L in prostate cancer
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Damien Destouches1,2,3, Maha Sader1,3, Stéphane Terry4, Charles Marchand1,2, Pascale Maillé1,2,5, Pascale Soyeux1,2, Gilles Carpentier1,3, Fannie Semprez1,2, Jocelyn Céraline7, Yves Allory1,2,5, José Courty1,3, Alexandre De La Taille1,2,6, Francis Vacherot1,2
1Université Paris-Est, UPEC, Créteil, F-94000, France
2INSERM, U955, Equipe 7, Créteil, F-94000, France
3CNRS, ERL 9215, Laboratoire de Recherche sur la Croissance Cellulaire, la Réparation et la Régénération Tissulaires (CRRET), Créteil, F-94000, France
4INSERM, U1186, Gustave Roussy Cancer Campus, Villejuif, F-94805, France
5AP-HP, Hôpital H. Mondor – A. Chenevier, Département de Pathologie, Créteil, F-94000, France
6AP-HP, Hôpital H. Mondor – A. Chenevier, Département d’Urologie, Créteil, F-94000, France
7INSERM, U1113, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, Strasbourg, F-67000, France
Damien Destouches, email: firstname.lastname@example.org
Keywords: prostate cancer, NPM1, phosphorylated NPM1, N6L, androgen receptor
Received: September 29, 2015 Accepted: February 29, 2016 Published: March 14, 2016
Despite the advent of several new treatment options over the past years, advanced/metastatic prostate carcinoma (PCa) still remains incurable, which justifies the search for novel targets and therapeutic molecules. Nucleophosmin (NPM1) is a shuttling nucleoprotein involved in tumor growth and its targeting could be a potential approach for cancer therapy. We previously demonstrated that the multivalent pseudopeptide N6L binds to NPM1 potently affecting in vitro and in vivo tumor cell growth of various tumor types as well as angiogenesis. Furthermore, NPM1 binds to androgen receptor (AR) and modulate its activity. In this study, we first investigated the implication of the NPM1 and its Thr199 and Thr234/237 phosphorylated forms in PCa. We showed that phosphorylated forms of NPM1 interact with androgen receptor (AR) in nucleoplasm. N6L treatment of prostate tumor cells led to inhibition of NPM1 phosphorylation in conjunction with inhibition of AR activity. We also found that total and phosphorylated NPM1 were overexpressed in castration-resistant PCa. Assessment of the potential therapeutic role of N6L in PCa indicated that N6L inhibited tumor growth both in vitro and in vivo when used either alone or in combination with the standard-of-care first- (hormonotherapy) and second-line (docetaxel) treatments for advanced PCa. Our findings reveal the role of Thr199 and Thr234/237 phosphorylated NPM1 in PCa progression and define N6L as a new drug candidate for PCa therapy.
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