PRKRA/PACT expression promotes chemoresistance of mucinous ovarian cancer

Takeshi Hisamatsu, Michael McGuire, Sherry Y. Wu, Rajesha Rupaimoole, Sunila Pradeep, Emine Bayraktar, Kyunghee Noh, Wei Hu, Jean M. Hansen, Yasmin Lyons, Kshipra M. Gharpure, Archana S. Nagaraja, Lingegowda S. Mangala, Takashi Mitamura, Cristian Rodriguez-Aguayo, Young Gyu Eun, Johnathon Rose, Geoffrey Bartholomeusz, Cristina Ivan, Ju Seog LeeKoji Matsuo, Michael Frumovitz, Kwong K. Wong, Gabriel Lopez-Berestein, Anil K. Sood

Research output: Contribution to journalArticlepeer-review

24 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)162-172
Number of pages11
JournalMolecular cancer therapeutics
Volume18
Issue number1
DOIs
StatePublished - Jan 2019
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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