title: Over-expression of DNA-PKcs in renal cell carcinoma regulates mTORC2 activation, HIF-2α expression and cell proliferation.
abstract: Here, we demonstrated that DNA-PKcs is over-expressed in multiple human renal cell carcinoma (RCC) tissues and in primary/established human RCCs. Pharmacological or genetic inhibition of DNA-PKcs suppressed proliferation of RCC cells. DNA-PKcs was in the complex of mTOR and SIN1, mediating mTORC2 activation and HIF-2α expression in RCC cells. Inhibiting or silencing DNA-PKcs suppressed AKT Ser-473 phosphorylation and HIF-2α expression. In vivo, DNA-PKcs knockdown or oral administration of the DNA-PKcs inhibitor NU-7441 inhibited AKT Ser-473 phosphorylation, HIF-2α expression and 786-0 RCC xenograft growth in nude mice. We showed that miRNA-101 level was decreased in RCC tissues/cells, which could be responsible for DNA-PKcs overexpression and DNA-PKcs mediated oncogenic actions in RCC cells. We show that DNA-PKcs over-expression regulates mTORC2-AKT activation, HIF-2α expression and RCC cell proliferation.
authors.affiliation: Department of Urology, The Second Affiliated Hospital of Nantong University, Nantong 226000, China.
authors.forename: Bing
authors.initials: B
authors.lastname: Zheng
authors.affiliation: Department of pathophysiology, Nantong University School of Medicine, Nantong, China.
authors.forename: Jia-Hui
authors.initials: JH
authors.lastname: Mao
authors.affiliation: Department of pathophysiology, Nantong University School of Medicine, Nantong, China.
authors.forename: Xiao-Qing
authors.initials: XQ
authors.lastname: Li
authors.affiliation: Department of Urology, The Second Affiliated Hospital of Nantong University, Nantong 226000, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Qian
authors.affiliation: Department of Urology, The Second Affiliated Hospital of Nantong University, Nantong 226000, China.
authors.forename: Hua
authors.initials: H
authors.lastname: Zhu
authors.affiliation: Department of Urology, The Second Affiliated Hospital of Nantong University, Nantong 226000, China.
authors.forename: Dong-Hua
authors.initials: DH
authors.lastname: Gu
authors.affiliation: Department of Urology, The Second Affiliated Hospital of Nantong University, Nantong 226000, China.
authors.forename: Xiao-Dong
authors.initials: XD
authors.lastname: Pan
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D002292:Carcinoma, Renal Cell / Q000378:metabolism*; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002867:Chromones / Q000737:chemistry; D051747:DNA-Activated Protein Kinase / Q000378:metabolism*; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007680:Kidney Neoplasms / Q000378:metabolism*; D000076225:Mechanistic Target of Rapamycin Complex 2 / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009025:Morpholines / Q000737:chemistry; D009368:Neoplasm Transplantation; D009687:Nuclear Proteins / Q000378:metabolism*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051792:Basic Helix-Loop-Helix Proteins; D053148:Caspase 3; D002867:Chromones; D051747:DNA-Activated Protein Kinase; D000076225:Mechanistic Target of Rapamycin Complex 2; D035683:MicroRNAs; D009025:Morpholines; D009687:Nuclear Proteins; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D000099162:Endothelial PAS Domain-Containing Protein 1; C499693:8-dibenzothiophen-4-yl-2-morpholin-4-yl-chromen-4-one; C493277:MAPKAP1 protein, human; C534072:MIRN101 microRNA, human; C546842:MTOR protein, human; C494918:AKT1 protein, human; C497263:PRKDC protein, human; C505407:CASP3 protein, human