title: Aberrantly activated pSTAT3-Ser727 in human endometrial cancer is suppressed by HO-3867, a novel STAT3 inhibitor.
abstract: 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.
authors.affiliation: Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Comprehensive Cancer Center and Solid Tumor Biology Program, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
authors.forename: Brent J
authors.initials: BJ
authors.lastname: Tierney
authors.affiliation: Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Comprehensive Cancer Center and Solid Tumor Biology Program, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
authors.forename: Georgia A
authors.initials: GA
authors.lastname: McCann
authors.affiliation: Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Comprehensive Cancer Center and Solid Tumor Biology Program, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
authors.forename: Shan
authors.initials: S
authors.lastname: Naidu
authors.affiliation: Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Comprehensive Cancer Center and Solid Tumor Biology Program, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
authors.forename: Kellie S
authors.initials: KS
authors.lastname: Rath
authors.affiliation: Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Comprehensive Cancer Center and Solid Tumor Biology Program, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
authors.forename: Uksha
authors.initials: U
authors.lastname: Saini
authors.affiliation: Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Comprehensive Cancer Center and Solid Tumor Biology Program, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
authors.forename: Ross
authors.initials: R
authors.lastname: Wanner
authors.affiliation: Department of Radiology, The Dartmouth Medical School, Hanover, NH, USA.
authors.forename: Periannan
authors.initials: P
authors.lastname: Kuppusamy
authors.affiliation: Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Comprehensive Cancer Center and Solid Tumor Biology Program, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
authors.forename: Adrian
authors.initials: A
authors.lastname: Suarez
authors.affiliation: Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Comprehensive Cancer Center and Solid Tumor Biology Program, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Goodfellow
authors.affiliation: Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Comprehensive Cancer Center and Solid Tumor Biology Program, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
authors.forename: David E
authors.initials: DE
authors.lastname: Cohn
authors.affiliation: Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Comprehensive Cancer Center and Solid Tumor Biology Program, The Ohio State University Wexner Medical Center, Columbus, OH, USA. Electronic address: selvendiran.karuppaiyah@osumc.edu.
authors.forename: Karuppaiyah
authors.initials: K
authors.lastname: Selvendiran
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D016889:Endometrial Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D005260:Female; D006801:Humans; D051379:Mice; D010881:Piperidones / Q000627:therapeutic use*; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*
chemical_list: C541427:(3,5-bis((4-fluorophenyl)methylidene)-1-((1-hydroxy-2,2,5,5-tetramethyl-2,5-dihydro-1H-pyrrol-3-yl)methyl)piperidin-4-one); D010881:Piperidones; D050796:STAT3 Transcription Factor
keywords: Curcumin analog; Endometrial cancer; HO-3867; STAT3; STAT3 inhibitor