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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / metabolism
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Animals
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Apoptosis
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Basic Helix-Loop-Helix Transcription Factors / metabolism*
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Carcinoma, Renal Cell / metabolism*
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Caspase 3 / metabolism
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Cell Line, Tumor
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Cell Proliferation
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Chromones / chemistry
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DNA-Activated Protein Kinase / metabolism*
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Female
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Gene Expression Profiling
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Gene Expression Regulation, Neoplastic
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Humans
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Kidney Neoplasms / metabolism*
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Mechanistic Target of Rapamycin Complex 2 / metabolism*
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Mice
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Mice, Nude
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MicroRNAs / genetics
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MicroRNAs / metabolism*
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Morpholines / chemistry
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Neoplasm Transplantation
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Nuclear Proteins / metabolism*
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Phosphorylation
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Proto-Oncogene Proteins c-akt / metabolism
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TOR Serine-Threonine Kinases / metabolism
Substances
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8-dibenzothiophen-4-yl-2-morpholin-4-yl-chromen-4-one
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Adaptor Proteins, Signal Transducing
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Basic Helix-Loop-Helix Transcription Factors
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Chromones
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MAPKAP1 protein, human
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MIRN101 microRNA, human
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MicroRNAs
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Morpholines
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Nuclear Proteins
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endothelial PAS domain-containing protein 1
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MTOR protein, human
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AKT1 protein, human
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DNA-Activated Protein Kinase
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Mechanistic Target of Rapamycin Complex 2
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PRKDC protein, human
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Proto-Oncogene Proteins c-akt
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TOR Serine-Threonine Kinases
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CASP3 protein, human
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Caspase 3