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Assessment of Mitochondrial Functions and Cell Viability in Renal Cells Overexpressing Protein Kinase C Isozymes
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Assessment of Mitochondrial Functions and Cell Viability in Renal Cells Overexpressing Protein Kinase C Isozymes

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Over-expression of DNA-PKcs in renal cell carcinoma regulates mTORC2 activation, HIF-2α expression and cell

Bing Zheng1, Jia-Hui Mao2, Xiao-Qing Li2

  • 1Department of Urology, The Second Affiliated Hospital of Nantong University, Nantong 226000, China.

Scientific Reports
|July 15, 2016
PubMed

Insights

DNA-PKcs overexpression drives renal cell carcinoma (RCC) proliferation by activating mTORC2-AKT and HIF-2α pathways. Inhibiting DNA-PKcs suppressed tumor growth, offering a potential therapeutic strategy for RCC.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Renal cell carcinoma (RCC) is a significant health concern with complex molecular underpinnings.
  • DNA-dependent protein kinase catalytic subunit (DNA-PKcs) is implicated in various cellular processes, but its role in RCC requires further elucidation.

Purpose of the Study:

  • To investigate the role of DNA-PKcs in the pathogenesis and progression of human renal cell carcinoma.
  • To explore the molecular mechanisms by which DNA-PKcs influences RCC cell proliferation and tumor growth.

Main Methods:

  • Analysis of DNA-PKcs expression in human RCC tissues and cell lines.
  • Pharmacological and genetic inhibition of DNA-PKcs.
  • Western blotting to assess protein phosphorylation and expression (e.g., AKT Ser-473, HIF-2α).
  • In vivo studies using RCC xenograft models in nude mice.

Main Results:

  • DNA-PKcs is overexpressed in human RCC tissues and cell lines.
  • Inhibition of DNA-PKcs suppressed RCC cell proliferation, AKT Ser-473 phosphorylation, and HIF-2α expression.
  • DNA-PKcs interacts with mTOR and SIN1, mediating mTORC2 activation.
  • In vivo, DNA-PKcs inhibition reduced tumor growth and key molecular markers.
  • Decreased miRNA-101 levels correlate with DNA-PKcs overexpression in RCC.

Conclusions:

  • DNA-PKcs overexpression is a key driver of RCC proliferation and tumor growth.
  • The DNA-PKcs/mTORC2/AKT/HIF-2α axis represents a critical pathway in RCC pathogenesis.
  • Targeting DNA-PKcs, potentially modulated by miRNA-101, offers a promising therapeutic avenue for renal cell carcinoma.

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