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.
Highlights
Renal cell carcinoma (RCC) is the most common renal malignancy
We show that DNA-PKcs is over-expressed in multiple human renal cell carcinoma (RCC) tissues and cells, regulating mammalian target of rapamycin (mTOR) complex 2-AKT activation, hypoxia-inducible factor-2α(HIF-2α)expression and RCC cell progression
DNA-PKcs mRNA level was over-expressed in above HCC cells (Fig. 1F). These results show that DNA-PKcs is over-expressed in human RCC tissues and RCC cells
Summary
DNA-PKcs over-expression in human RCC cells and tissues. First, we examined the expression of DNA-PKcs in human RCC tissues. Note that above experiments were repeated in A498 cells and primary human HCC cells, and similar results were obtained (Data not shown) Together, these results indicate that DNA-PKcs is in the complex of mTORC2, regulating AKT Ser-473 phosphorylation and HIF-2αexpression in RCC cells. We showed that DNA-PKcs formed a complex with mTOR and SIN1 in both human RCC tissues and RCC cells, and was required for mTORC2 activation (AKT Ser-473 phosphorylation) and HIF-2αexpression. We showed that miR-101 level was significantly lower in human RCC tissues, and in established or primary RCC cells, which might be a reason for DNA-PKcs over-expression. Introduction of miR-101 in RCC cells downregulated DNA-PKcs expression, and inhibited AKT activation, HIF-2αexpression and cell proliferation. Our results demonstrate that DNA-PKcs over-expression in RCC cells regulates mTORC2-AKT activation, HIF-2αexpression and RCC cell progression. DNA-PKcs might be a valuable target for RCC treatment
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