Open Access

Downregulation of Keap1 contributes to poor prognosis and Axitinib resistance of renal cell carcinoma via upregulation of Nrf2 expression

  • Authors:
    • Haipeng Huang
    • Yunhong Wu
    • Weijin Fu
    • Xiaoming Wang
    • Liquan Zhou
    • Xiaolong Xu
    • Fu Huang
    • Yi Wu
  • View Affiliations

  • Published online on: March 14, 2019     https://doi.org/10.3892/ijmm.2019.4134
  • Pages: 2044-2054
  • Copyright: © Huang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Kelch‑like ECH‑associated protein 1 (Keap1)/nuclear factor erythroid 2‑related factor 2 (Nrf2) signaling has a protective effect on normal cells. A number of previous studies demonstrated that Keap1/Nrf2 signaling is associated with drug resistance in numerous tumors. The aim of the present study was to investigate the roles of Keap1 in renal cell carcinoma (RCC) and its effect on sensitivity to chemotherapy. Reverse transcription‑quantitative polymerase chain reaction was used to detect the mRNA expression of Keap1 in 45 cases of RCC tumors and adjacent normal tissues. A total of five randomly selected patients with RCC, five RCC cell lines and normal renal tubular cells were examined to detect the protein and mRNA expressions of Keap1. The 5‑year survival rate was analyzed by Kaplan‑Meier analysis. The cell viability was assessed by a Cell Counting kit‑8 assay. The cell apoptosis and reactive oxygen species (ROS) were determined by flow cytometry. The expressions of associated proteins were determined by western blot analysis. It was identified that in RCC tissues and RCC cell lines, the expression of Keap1 was downregulated, which was considered to be associated with poor prognosis. In total, 1 µM Axitinib significantly decreased cell viability, promoted ROS release and induced cell apoptosis in ACHN cells. Silencing Keap1 was able to reverse the inhibitory effect of Axitinib and enhance the protein expressions of Nrf2, NAD(P)H dehydrogenase [quinone] 1 and heme oxygenase 1. However, silencing Nrf2 increased the cell sensitivity to Axitinib. Under Axitinib condition, overexpressing Nrf2 was able to increase cell viability; however, overexpressing Keap1 resulted in an opposite effect. Keap1 serves as a tumor suppressor; its low expression was associated with poor prognosis and a decreased sensitivity of RCC cells to Axitinib. A possible mechanism underlying Axitinib resistance may involve Nrf2 overexpression.
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May-2019
Volume 43 Issue 5

Print ISSN: 1107-3756
Online ISSN:1791-244X

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Spandidos Publications style
Huang H, Wu Y, Fu W, Wang X, Zhou L, Xu X, Huang F and Wu Y: Downregulation of Keap1 contributes to poor prognosis and Axitinib resistance of renal cell carcinoma via upregulation of Nrf2 expression. Int J Mol Med 43: 2044-2054, 2019
APA
Huang, H., Wu, Y., Fu, W., Wang, X., Zhou, L., Xu, X. ... Wu, Y. (2019). Downregulation of Keap1 contributes to poor prognosis and Axitinib resistance of renal cell carcinoma via upregulation of Nrf2 expression. International Journal of Molecular Medicine, 43, 2044-2054. https://doi.org/10.3892/ijmm.2019.4134
MLA
Huang, H., Wu, Y., Fu, W., Wang, X., Zhou, L., Xu, X., Huang, F., Wu, Y."Downregulation of Keap1 contributes to poor prognosis and Axitinib resistance of renal cell carcinoma via upregulation of Nrf2 expression". International Journal of Molecular Medicine 43.5 (2019): 2044-2054.
Chicago
Huang, H., Wu, Y., Fu, W., Wang, X., Zhou, L., Xu, X., Huang, F., Wu, Y."Downregulation of Keap1 contributes to poor prognosis and Axitinib resistance of renal cell carcinoma via upregulation of Nrf2 expression". International Journal of Molecular Medicine 43, no. 5 (2019): 2044-2054. https://doi.org/10.3892/ijmm.2019.4134