nu-7441 and Kidney-Neoplasms

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.

Topics: Adaptor Proteins, Signal Transducing; Animals; Apoptosis; Basic Helix-Loop-Helix Transcription Factors; Carcinoma, Renal Cell; Caspase 3; Cell Line, Tumor; Cell Proliferation; Chromones; DNA-Activated Protein Kinase; Female; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Kidney Neoplasms; Mechanistic Target of Rapamycin Complex 2; Mice; Mice, Nude; MicroRNAs; Morpholines; Neoplasm Transplantation; Nuclear Proteins; Phosphorylation; Proto-Oncogene Proteins c-akt; TOR Serine-Threonine Kinases