Data from PRKRA/PACT Expression Promotes Chemoresistance of Mucinous Ovarian Cancer
Year: 2023
Type: other
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.
Authors: 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 Lee, Koji Matsuo, Michael Frumovitz, Kwong K. Wong, Gabriel Lopez-Berestein, Anil K. Sood
Language: English
Subfield: Reproductive Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: gold
OpenAlex ID: W4362494956