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Mol Cancer Ther. 2019 Jan;18(1):162-172. doi: 10.1158/1535-7163.MCT-17-1050. Epub 2018 Oct 10.

PRKRA/PACT Expression Promotes Chemoresistance of Mucinous Ovarian Cancer.

Author information

1
Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
2
Department of Obstetrics and Gynecology, Medical College of Wisconsin, Milwaukee, Wisconsin.
3
Gene Therapy Research Unit, Korea Research Institute of Bioscience & Biotechnology, Daejeon, Republic of Korea.
4
Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, Texas.
5
Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
6
Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
7
Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Southern California, Los Angeles, California.
8
Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas. asood@mdanderson.org.
9
Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Abstract

For mucinous ovarian cancer (MOC), standard platinum-based therapy is largely ineffective. We sought to identify possible mechanisms of oxaliplatin resistance of MOC and develop strategies to overcome this resistance. A kinome-based siRNA library screen was carried out using human MOC cells to identify novel targets to enhance the efficacy of chemotherapy. In vitro and in vivo validations of antitumor effects were performed using mouse MOC models. Specifically, the role of PRKRA/PACT in oxaliplatin resistance was interrogated. We focused on PRKRA, a known activator of PKR kinase, and its encoded protein PACT because it was one of the five most significantly downregulated genes in the siRNA screen. In orthotopic mouse models of MOC, we observed a significant antitumor effect of PRKRA siRNA plus oxaliplatin. In addition, expression of miR-515-3p was regulated by PACT-Dicer interaction, and miR-515-3p increased the sensitivity of MOC to oxaliplatin. Mechanistically, miR-515-3p regulated chemosensitivity, in part, by targeting AXL. The PRKRA/PACT axis represents an important therapeutic target in MOC to enhance sensitivity to oxaliplatin.

PMID:
30305341
PMCID:
PMC6318044
[Available on 2020-01-01]
DOI:
10.1158/1535-7163.MCT-17-1050

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