The Wnt inhibitor LGK-974 enhances radiosensitivity of HepG2 cells by modulating Nrf2 signaling

  • Authors:
    • Dan Tian
    • Ying Shi
    • Dexi Chen
    • Qiang Liu
    • Feiyue Fan
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  • Published online on: June 14, 2017     https://doi.org/10.3892/ijo.2017.4042
  • Pages: 545-554
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Abstract

Nuclear factor (erythroid-derived 2)-like 2 (NRF2) is a master regulator of antioxidant and detoxification activities that can eliminate reactive oxygen species (ROS) produced via irradiation. However, Nrf2 overexpression in liver cancer cells may cause both radioresistance and chemoresistance. Reducing Nrf2 levels can enhance the radiosensitivity of HepG2 cells. Wingless/int-3A (Wnt3A) is a Wnt family protein that mainly activates the canonical Wnt signaling pathway. Recent studies showed that the Axin1-GSK-3β protein complex, a component of the canonical Wnt signaling pathway, can capture Nrf2 and facilitate its ubiquitination and proteasomal degradation in the cytoplasm. This protein complex is degraded upon activation of the Wnt signaling pathway. In the present study, we treated HepG2 cells with the Wnt3A inhibitor LGK-974, an effective and specific PORCN inhibitor that can prevent the formation of a proper folding of the Wnt protein in the endoplasmic reticulum. We found that HepG2 cells became more sensitive to radiation with increasing LGK-974 concentrations. Upon 2 Gy or 4 Gy irradiation, the cells treated with LGK-974 more frequently underwent apoptosis and grew less rapidly. PCR and western blot results showed that inhibiting the secretion of Wnt3A blocked the Wnt signaling pathway and prevented Nrf2 signaling. Notably, the Wnt inhibitor may serve as a radiosensitizing drug.
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August-2017
Volume 51 Issue 2

Print ISSN: 1019-6439
Online ISSN:1791-2423

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Spandidos Publications style
Tian D, Shi Y, Chen D, Liu Q and Fan F: The Wnt inhibitor LGK-974 enhances radiosensitivity of HepG2 cells by modulating Nrf2 signaling. Int J Oncol 51: 545-554, 2017.
APA
Tian, D., Shi, Y., Chen, D., Liu, Q., & Fan, F. (2017). The Wnt inhibitor LGK-974 enhances radiosensitivity of HepG2 cells by modulating Nrf2 signaling. International Journal of Oncology, 51, 545-554. https://doi.org/10.3892/ijo.2017.4042
MLA
Tian, D., Shi, Y., Chen, D., Liu, Q., Fan, F."The Wnt inhibitor LGK-974 enhances radiosensitivity of HepG2 cells by modulating Nrf2 signaling". International Journal of Oncology 51.2 (2017): 545-554.
Chicago
Tian, D., Shi, Y., Chen, D., Liu, Q., Fan, F."The Wnt inhibitor LGK-974 enhances radiosensitivity of HepG2 cells by modulating Nrf2 signaling". International Journal of Oncology 51, no. 2 (2017): 545-554. https://doi.org/10.3892/ijo.2017.4042