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2014 ; 135
(1
): 133-41
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Aberrantly activated pSTAT3-Ser727 in human endometrial cancer is suppressed by
HO-3867, a novel STAT3 inhibitor
#MMPMID25038288
Tierney BJ
; McCann GA
; Naidu S
; Rath KS
; Saini U
; Wanner R
; Kuppusamy P
; Suarez A
; Goodfellow PJ
; Cohn DE
; Selvendiran K
Gynecol Oncol
2014[Oct]; 135
(1
): 133-41
PMID25038288
show ga
OBJECTIVE: Constitutive activation of STAT3 is a hallmark of various human
cancers, however an increased pSTAT3 expression in high grade human endometrial
cancer has not been reported. In the present study, we examine the expression of
STAT family of proteins in endometrial cancer cell lines and the efficacy of
HO-3867, a novel STAT3 inhibitor designed in our lab. METHODS: Expression of STAT
family proteins was evaluated via Western blot. The cell viability,
post-treatment with HO-3867, was assessed using MTT, cell-cycle profile and
Annexin assay. In vivo efficacy of HO-3867 was evaluated using xenograft mice.
RESULTS: Expression of activated STATs was inconsistent among the cell lines and
18 human endometrial cancer specimens tested. While pSTAT3 Tyr705 was not
expressed in any of the cell lines, pSTAT3 Ser727 was highly expressed in
endometrial cancer cell lines and tumor specimens. HO-3867 decreased the
expression of pSTAT3 Ser727 while total STAT3 remained constant; cell viability
decreased by 50-80% and induced G2/M arrest in 55% of Ishikawa cells at the G2/M
cell cycle checkpoint. There was an increase in p53, a decrease in Bcl2 and
Bcl-xL, and cleavage of caspase-3, caspase-7 and PARP. HO-3867 mediated a
dosage-dependent inhibition of the growth of xenografted endometrial tumors.
CONCLUSIONS: HO-3867 treatment decreases the high levels of pSTAT3 Ser727 in
endometrial cancer cells by inducing cell cycle arrest and apoptosis. This
suggests a specific role of serine-phosphorylated STAT3, independent of tyrosine
phosphorylation in the oncogenesis of endometrial cancer. HO-3867 could
potentially serve as an adjunctive targeted therapy.