Inhibition of STAT1 sensitizes renal cell carcinoma cells to radiotherapy and chemotherapy

Abstract

Renal cell carcinoma is resistant to chemotherapy and radiotherapy. STAT1 is overexpressed in human RCC tissue. Downregulation of STAT1 expression could significantly increase the radiosensitivity in RCC cell lines. To further investigate the function of STAT1 in RCC resistance to chemoradiotherapy, a stable STAT1 knockdown cell line was established. Knockdown of STAT1 led to significant growth suppression in vitro and in vivo. Inhibition of STAT1 sensitized 786-O cells to radiotherapy and Taxol treatment. Cells with low STAT1 expression accumulated more strongly in the G₂/M phase after treatment with chemotherapy and radiotherapy. The Human Cell Cycle and DNA Damage Signaling Pathway Real-time PCR arrays were performed and 3 genes upregulated and 16 genes downregulated after STAT1 knockdown were selected. Functional gene grouping showed that genes involved in the M phase, S phase and DNA replication did not differ between the two cell lines. G₁ phase related genes ANAPC2, CCNE1, CUL1 were downregulated, and G₂/M checkpoint genes p21, GADD45A and Rb were strongly reduced by STAT1 knockdown. DNA damage-related genes GADD45A, MAP2K6, were significantly downregulated. The results prove that overexpression of STAT1 in human RCC is associated with the chemoradioresistance. Targeting of STAT1 might be a potential strategy to sensitize RCC to chemotherapy and radiotherapy.

Keywords: :

• cell cycle
• chemoresistance
• DNA damage
• radioresistance
• renal cell carcinoma
• signal transducer and activator of transcription 1

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.

Acknowledgments

This work was supported by National Natural Science Foundation (30800280, 81021061), and the Scientific Research Foundation for the Returned Overseas Chinese Scholars, State Education Ministry, P.R. China.