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

Tian,Dan; Shi,Ying; Chen,Dexi; Liu,Qiang; Fan,Feiyue

doi:10.3892/ijo.2017.4042

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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Affiliations: Institute of Radiation Medicine, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), Tianjin 300192, P.R. China, Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing 100069, P.R. China, Institute of Laboratory Animal Sciences, Peking Union Medical College (PUMC) and Chinese Academy of Medical Sciences (CAMS), Beijing 100069, P.R. China
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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