title: Implication of NPM1 phosphorylation and preclinical evaluation of the nucleoprotein antagonist N6L in prostate cancer.
abstract: 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.
authors.affiliation: Université Paris-Est, UPEC, Créteil, F-94000, France.|INSERM, U955, Equipe 7, Créteil, F-94000, France.|CNRS, ERL 9215, Laboratoire de Recherche sur la Croissance Cellulaire, la Réparation et la Régénération Tissulaires (CRRET), Créteil, F-94000, France.
authors.forename: Damien
authors.initials: D
authors.lastname: Destouches
authors.affiliation: Université Paris-Est, UPEC, Créteil, F-94000, France.|CNRS, ERL 9215, Laboratoire de Recherche sur la Croissance Cellulaire, la Réparation et la Régénération Tissulaires (CRRET), Créteil, F-94000, France.
authors.forename: Maha
authors.initials: M
authors.lastname: Sader
authors.affiliation: INSERM, U1186, Gustave Roussy Cancer Campus, Villejuif, F-94805, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Terry
authors.affiliation: Université Paris-Est, UPEC, Créteil, F-94000, France.|INSERM, U955, Equipe 7, Créteil, F-94000, France.
authors.forename: Charles
authors.initials: C
authors.lastname: Marchand
authors.affiliation: Université Paris-Est, UPEC, Créteil, F-94000, France.|INSERM, U955, Equipe 7, Créteil, F-94000, France.|AP-HP, Hôpital H. Mondor - A. Chenevier, Département de Pathologie, Créteil, F-94000, France.
authors.forename: Pascale
authors.initials: P
authors.lastname: Maillé
authors.affiliation: Université Paris-Est, UPEC, Créteil, F-94000, France.|INSERM, U955, Equipe 7, Créteil, F-94000, France.
authors.forename: Pascale
authors.initials: P
authors.lastname: Soyeux
authors.affiliation: Université Paris-Est, UPEC, Créteil, F-94000, France.|CNRS, ERL 9215, Laboratoire de Recherche sur la Croissance Cellulaire, la Réparation et la Régénération Tissulaires (CRRET), Créteil, F-94000, France.
authors.forename: Gilles
authors.initials: G
authors.lastname: Carpentier
authors.affiliation: Université Paris-Est, UPEC, Créteil, F-94000, France.|INSERM, U955, Equipe 7, Créteil, F-94000, France.
authors.forename: Fannie
authors.initials: F
authors.lastname: Semprez
authors.affiliation: INSERM, U1113, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, Strasbourg, F-67000, France.
authors.forename: Jocelyn
authors.initials: J
authors.lastname: Céraline
authors.affiliation: Université Paris-Est, UPEC, Créteil, F-94000, France.|INSERM, U955, Equipe 7, Créteil, F-94000, France.|AP-HP, Hôpital H. Mondor - A. Chenevier, Département de Pathologie, Créteil, F-94000, France.
authors.forename: Yves
authors.initials: Y
authors.lastname: Allory
authors.affiliation: Université Paris-Est, UPEC, Créteil, F-94000, France.|CNRS, ERL 9215, Laboratoire de Recherche sur la Croissance Cellulaire, la Réparation et la Régénération Tissulaires (CRRET), Créteil, F-94000, France.
authors.forename: José
authors.initials: J
authors.lastname: Courty
authors.affiliation: Université Paris-Est, UPEC, Créteil, F-94000, France.|INSERM, U955, Equipe 7, Créteil, F-94000, France.|AP-HP, Hôpital H. Mondor - A. Chenevier, Département d'Urologie, Créteil, F-94000, France.
authors.forename: Alexandre
authors.initials: A
authors.lastname: De La Taille
authors.affiliation: Université Paris-Est, UPEC, Créteil, F-94000, France.|INSERM, U955, Equipe 7, Créteil, F-94000, France.
authors.forename: Francis
authors.initials: F
authors.lastname: Vacherot
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D000077143:Docetaxel; D006801:Humans; D008297:Male; D008819:Mice, Nude; D009687:Nuclear Proteins / Q000378:metabolism*; D000090243:Nucleophosmin; D009698:Nucleoproteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010455:Peptides / Q000378:metabolism / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D011485:Protein Binding; D011944:Receptors, Androgen / Q000378:metabolism; D043823:Taxoids / Q000494:pharmacology; D013912:Threonine / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: C410798:AR protein, human; D000970:Antineoplastic Agents; C580583:N6L peptide; C000716967:NPM1 protein, human; C000715570:Npm1 protein, mouse; D009687:Nuclear Proteins; D009698:Nucleoproteins; D010455:Peptides; D011944:Receptors, Androgen; D043823:Taxoids; D000090243:Nucleophosmin; D000077143:Docetaxel; D013912:Threonine
keywords: N6L; NPM1; androgen receptor; phosphorylated NPM1; prostate cancer