PRKRA /PACT Expression Promotes Chemoresistance of Mucinous Ovarian Cancer

• Published in: Molecular cancer therapeutics Vol. 18; no. 1; pp. 162 - 172
• Main Authors: Hisamatsu, Takeshi, McGuire, Michael, Wu, Sherry Y, Rupaimoole, Rajesha, Pradeep, Sunila, Bayraktar, Emine, Noh, Kyunghee, Hu, Wei, Hansen, Jean M, Lyons, Yasmin, Gharpure, Kshipra M, Nagaraja, Archana S, Mangala, Lingegowda S, Mitamura, Takashi, Rodriguez-Aguayo, Cristian, Eun, Young Gyu, Rose, Johnathon, Bartholomeusz, Geoffrey, Ivan, Cristina, Lee, Ju-Seog, Matsuo, Koji, Frumovitz, Michael, Wong, Kwong K, Lopez-Berestein, Gabriel, Sood, Anil K
• Format: Journal Article
• Language: English
• Published: United States 01.01.2019
• Subjects: Adenocarcinoma, Mucinous - genetics; Adenocarcinoma, Mucinous - metabolism; Adenocarcinoma, Mucinous - pathology; Animals; Cell Line, Tumor; Cell Survival; DEAD-box RNA Helicases - metabolism; Drug Resistance, Neoplasm; Female; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; Humans; Mice; MicroRNAs - genetics; Ovarian Neoplasms - genetics; Ovarian Neoplasms - metabolism; Ovarian Neoplasms - pathology; Oxaliplatin; Proto-Oncogene Proteins - genetics; Receptor Protein-Tyrosine Kinases - genetics; Ribonuclease III - metabolism; RNA, Small Interfering - pharmacology; RNA-Binding Proteins - genetics; RNA-Binding Proteins - metabolism; Up-Regulation
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.MCT-17-1050

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. and validations of antitumor effects were performed using mouse MOC models. Specifically, the role of /PACT in oxaliplatin resistance was interrogated. We focused on , 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 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 /PACT axis represents an important therapeutic target in MOC to enhance sensitivity to oxaliplatin.