TY - JOUR
T1 - PTGER3 induces ovary tumorigenesis and confers resistance to cisplatin therapy through up-regulation Ras-MAPK/Erk-ETS1-ELK1/CFTR1 axis
AU - Rodriguez-Aguayo, Cristian
AU - Bayraktar, Emine
AU - Ivan, Cristina
AU - Aslan, Burcu
AU - Mai, Junhua
AU - He, Guangan
AU - Mangala, Lingegowda S.
AU - Jiang, Dahai
AU - Nagaraja, Archana S.
AU - Ozpolat, Bulent
AU - Chavez-Reyes, Arturo
AU - Ferrari, Mauro
AU - Mitra, Rahul
AU - Siddik, Zahid H.
AU - Shen, Haifa
AU - Yang, Xianbin
AU - Sood, Anil K.
AU - Lopez-Berestein, Gabriel
N1 - Funding Information:
This work was supported in part by grants from the National Institutes of Health / National Cancer Institute ( R44GM086937 , P50 CA093459 , U54 CA151668 , P50 CA083639 , P50 CA098258 , R21 CA180145 , UH3TR000943 , RO1CA160687 and U54 CA96300 ), the Cancer Prevention Research Institute of Texas ( RP120214 ), the FRANK McGraw Memorial Chair in Cancer Research , and the American Cancer Society Research Professor Award . This research was performed in the Flow Cytometry & Cellular Imaging Facility , which is supported in part by the National Institutes of Health through M. D. Anderson's Cancer Center Support Grant CA016672 . The funding institutions had not any role in study design, data collection, data analysis, interpretation or writing of the report in this study.
Funding Information:
This work was supported in part by grants from the National Institutes of Health/National Cancer Institute (R44GM086937, P50 CA093459, U54 CA151668, P50 CA083639, P50 CA098258, R21 CA180145, UH3TR000943, RO1CA160687 and U54 CA96300), the Cancer Prevention Research Institute of Texas (RP120214), the FRANK McGraw Memorial Chair in Cancer Research, and the American Cancer Society Research Professor Award. This research was performed in the Flow Cytometry & Cellular Imaging Facility, which is supported in part by the National Institutes of Health through M. D. Anderson's Cancer Center Support Grant CA016672. The funding institutions had not any role in study design, data collection, data analysis, interpretation or writing of the report in this study.
Publisher Copyright:
© 2018
PY - 2019/2
Y1 - 2019/2
N2 - 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.
AB - 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.
KW - CFTR
KW - Chemically modified siRNA
KW - Cisplatin resistance
KW - ELK1
KW - ETS1
KW - Ovarian cancer
KW - PTGER3
KW - RNA interference
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U2 - 10.1016/j.ebiom.2018.11.045
DO - 10.1016/j.ebiom.2018.11.045
M3 - Article
C2 - 30655206
AN - SCOPUS:85059851379
SN - 2352-3964
VL - 40
SP - 290
EP - 304
JO - EBioMedicine
JF - EBioMedicine
ER -