Antitumor effects of cyclin dependent kinase 9 inhibition in esophageal adenocarcinoma
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Zhimin Tong1, Devkumar Chatterjee2, Defeng Deng3, Omkara Veeranki1, Alicia Mejia1, Jaffer A Ajani4, Wayne Hofstetter5, Steven Lin2, Sushovan Guha6, Scott Kopetz4, Sunil Krishnan2, Dipen Maru1
1Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
2Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
3Department of System Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
4Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
5Department of Thoracic & Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
6Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
Dipen Maru, email: firstname.lastname@example.org
Keywords: cyclin dependent kinase 9, esophagus, adenocarcinoma, MCL-1, HIF-1 α
Received: May 11, 2016 Accepted: January 23, 2017 Published: February 23, 2017
Role of cyclin dependent kinase 9(CDK9) as a potential target in esophageal adenocarcinoma (EAC) is unknown. We investigated CDK9 protein expression in EAC and Barrett’s esophagus and role of CDK9 in oncogenic processes of EAC in vitro and in murine xenografts. The CDK9 expression was significantly higher in EAC as compared to Barrett’s esophagus in patient samples. Stable shCDK9 in SKGT4 reduced proliferation by 37% at day 4, increased apoptosis at 48 hours and induced G1 cell cycle arrest at 48 hours (58.4% vs. 45.8%) compared to controls SKGT4 cells. SKGT4-shCDK9 cell-derived tumors were significantly smaller than control SKGT4-derived tumors in xenografts (72.89mm3 vs. 270mm3). Pharmaceutical inhibition of CDK9 by Flavopiridol (0.1µm for 48 hours) and CAN508 (20 and 40µm for 72 hours) induced significant reduction in proliferation and 2-fold increase in apoptosis in SKGT4, FLO1 and OE33 cells. In xenograft models, CAN508 (60 mg/kg/dayx10 days) and Flavopiridol (4mg/kg/dayx10 days) caused 50.8% and 63.1% reduction in xenograft tumors as compared to control on post-treatment day 21. Reduction of MCL-1 and phosphorylated RNA polymerase II was observed with transient shCDK9 in SKGT4 cells but not with stable shCDK9. CAN508 (20 and 40 µm) and Flavopiridol (0.1, 0.2 and 0.3 µm) for 4 hours showed reduction in MCL-1 mRNA (84% and 96%) and protein. Mcl-1 overexpression conferred resistance to Flavopiridol (0.2 µm or 0.4 µm for 48 hours) and CAN 508 (20 or 40µm for 72 hours). Chromatin immunoprecipitation demonstrated significant reduction of binding of transcriptional factor HIF-1α to MCL-1 promoter in FLO-1 cells by CDK9 inhibitors.
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