FoxM1 and β-catenin predicts aggressiveness in Middle Eastern ovarian cancer and their co-targeting impairs the growth of ovarian cancer cells
Metrics: PDF 1844 views | HTML 1864 views | ?
Poyil Pratheeshkumar1,*, Sasidharan Padmaja Divya1,*, Sandeep Kumar Parvathareddy1, Norah M. Alhoshani1, Ismail A. Al-Badawi2, Asma Tulbah3, Fouad Al-Dayel3, Abdul K. Siraj1 and Khawla S. Al-Kuraya1
1Human Cancer Genomic Research, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
2Department of Obstetrics and Gynecology, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
3Department of Pathology, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
*These authors contributed equally to this work
Khawla S. Al-Kuraya, email: [email protected]
Keywords: EOC; FoxM1; β-catenin; thiostrepton; FH535
Received: July 14, 2017 Accepted: November 26, 2017 Published: December 16, 2017
Epithelial ovarian cancer (EOC) is a highly lethal disease with poor prognosis especially in advanced stage tumor. Emerging evidence has reported that aberrant upregulation of FoxM1 and β-catenin are closely associated with aggressiveness of human cancer. However, interplay between these factors in the aggressiveness of EOC is not fully illustrated. In this study, we show that FoxM1 is frequently increased in Middle Eastern EOC and associated with high proliferative index (p = 0.0007) and high grade tumor (p = 0.0024). Interestingly, FoxM1 is significantly associated with elevated nuclear β-catenin and the concomitant increase of FoxM1 and β-catenin is associated with advanced stage of EOC by immunohistochemical analysis of 261 samples of Saudi patients with EOC. Functional analysis showed that β-catenin is a direct transcriptional target of FoxM1 in EOC cell lines. FoxM1 inhibition either by specific inhibitor, thiostrepton or siRNA suppressed β-catenin expression, whereas overexpression of FoxM1 increased nuclear β-catenin expression. We identified two FoxM1 binding sites in the β-catenin promoter that specifically bound to FoxM1 protein. Down-regulation of FoxM1 using thiostrepton induced apoptosis and inhibited cell migration/invasion in EOC cells. Moreover, co-inhibition of FoxM1 by thiostrepton and β-catenin by FH535 significantly and synergistically inhibited EOC cell growth in vitro and in vivo. Collectively, our findings confer that co-targeting FoxM1/β-catenin signaling cascade may be a promising molecular therapeutic choice in advanced EOC.
All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.