title: Antitumor effects of cyclin dependent kinase 9 inhibition in esophageal adenocarcinoma.
abstract: 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.
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
authors.forename: Zhimin
authors.initials: Z
authors.lastname: Tong
authors.affiliation: Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
authors.forename: Devkumar
authors.initials: D
authors.lastname: Chatterjee
authors.affiliation: Department of System Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
authors.forename: Defeng
authors.initials: D
authors.lastname: Deng
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
authors.forename: Omkara
authors.initials: O
authors.lastname: Veeranki
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
authors.forename: Alicia
authors.initials: A
authors.lastname: Mejia
authors.affiliation: Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
authors.forename: Jaffer A
authors.initials: JA
authors.lastname: Ajani
authors.affiliation: Department of Thoracic & Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
authors.forename: Wayne
authors.initials: W
authors.lastname: Hofstetter
authors.affiliation: Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
authors.forename: Steven
authors.initials: S
authors.lastname: Lin
authors.affiliation: Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
authors.forename: Sushovan
authors.initials: S
authors.lastname: Guha
authors.affiliation: Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
authors.forename: Scott
authors.initials: S
authors.lastname: Kopetz
authors.affiliation: Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
authors.forename: Sunil
authors.initials: S
authors.lastname: Krishnan
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
authors.forename: Dipen
authors.initials: D
authors.lastname: Maru
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy*; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D017209:Apoptosis; D001471:Barrett Esophagus / Q000188:drug therapy*; D063646:Carcinogenesis; D045744:Cell Line, Tumor; D042863:Cyclin-Dependent Kinase 9 / Q000235:genetics / Q000378:metabolism*; D004938:Esophageal Neoplasms / Q000188:drug therapy*; D005260:Female; D005419:Flavonoids / Q000627:therapeutic use*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D008819:Mice, Nude; D008875:Middle Aged; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000235:genetics; D010880:Piperidines / Q000627:therapeutic use*; D034741:RNA, Small Interfering / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D005419:Flavonoids; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D010880:Piperidines; D034741:RNA, Small Interfering; C077990:alvocidib; C467969:CDK9 protein, human; D042863:Cyclin-Dependent Kinase 9
keywords: HIF-1 α; MCL-1; adenocarcinoma; cyclin dependent kinase 9; esophagus