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2016 ; 7
(43
): 69397-69411
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Implication of NPM1 phosphorylation and preclinical evaluation of the
nucleoprotein antagonist N6L in prostate cancer
#MMPMID26993766
Destouches D
; Sader M
; Terry S
; Marchand C
; Maillé P
; Soyeux P
; Carpentier G
; Semprez F
; Céraline J
; Allory Y
; Courty J
; De La Taille A
; Vacherot F
Oncotarget
2016[Oct]; 7
(43
): 69397-69411
PMID26993766
show ga
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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