PTGER3 induces ovary tumorigenesis and confers resistance to cisplatin therapy through up-regulation Ras-MAPK/Erk-ETS1-ELK1/CFTR1 axisResearch in context
Cristian Rodriguez-Aguayo,
Emine Bayraktar,
Cristina Ivan,
Burcu Aslan,
Junhua Mai,
Guangan He,
Lingegowda S. Mangala,
Dahai Jiang,
Archana S. Nagaraja,
Bulent Ozpolat,
Arturo Chavez-Reyes,
Mauro Ferrari,
Rahul Mitra,
Zahid H. Siddik,
Haifa Shen,
Xianbin Yang,
Anil K. Sood,
Gabriel Lopez-Berestein
Affiliations
Cristian Rodriguez-Aguayo
Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Emine Bayraktar
Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Medical Biology, Faculty of Medicine, University of Gaziantep, Gaziantep 27310, Turkey
Cristina Ivan
Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Burcu Aslan
Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Junhua Mai
Department of Nanomedicine, Houston Methodist Research Institute, Houston, TX 77030, USA
Guangan He
Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Lingegowda S. Mangala
Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Dahai Jiang
Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Archana S. Nagaraja
Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Bulent Ozpolat
Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Arturo Chavez-Reyes
Centro de Investigación y Estudios Avanzados del IPN, Unidad Monterrey, Apodaca, NL, CP. 66600, Mexico
Mauro Ferrari
Department of Nanomedicine, Houston Methodist Research Institute, Houston, TX 77030, USA
Rahul Mitra
Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Zahid H. Siddik
Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Haifa Shen
Department of Nanomedicine, Houston Methodist Research Institute, Houston, TX 77030, USA
Xianbin Yang
AM Biotechnologies LLC, 12521 Gulf Freeway, Houston, TX 77034, USA
Anil K. Sood
Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Gabriel Lopez-Berestein
Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Corresponding author at: Department of Experimental Therapeutics, P.O. Box 301429, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Background: Inflammatory mediator prostaglandin E2–prostaglandin E2 receptor EP3 (PTGER3) signaling is critical for tumor-associated angiogenesis, tumor growth, and chemoresistance. However, the mechanism underlying these effects in ovarian cancer is not known. Methods: An association between higher tumoral expression of PTGER3 and shorter patient survival in the ovarian cancer dataset of The Cancer Genome Atlas prompted investigation of the antitumor effects of PTGER3 downmodulation. PTGER3 mRNA and protein levels were higher in cisplatin-resistant ovarian cancer cells than in their cisplatin-sensitive counterparts. Findings: Silencing of PTGER3 via siRNA in cancer cells was associated with decreased cell growth and less invasiveness, as well as cell-cycle arrest and increased apoptosis, mediated through the Ras-MAPK/Erk-ETS1-ELK1/CFTR1 axis. Furthermore, sustained PTGER3 silencing with multistage vector and liposomal 2’-F-phosphorodithioate-siRNA–mediated silencing of PTGER3 combined with cisplatin resulted in robust antitumor effects in cisplatin-resistant ovarian cancer models. Interpretation: These findings identify PTGER3 as a potential therapeutic target in chemoresistant ovarian cancers expressing high levels of this oncogenic protein. Fund: National Institutes of Health/National Cancer Institute, USA. Keywords: PTGER3, Ovarian cancer, RNA interference, Chemically modified siRNA, Cisplatin resistance, ETS1, ELK1, CFTR
