期刊
INTERNATIONAL JOURNAL OF ONCOLOGY
卷 51, 期 2, 页码 545-554出版社
SPANDIDOS PUBL LTD
DOI: 10.3892/ijo.2017.4042
关键词
LGK-974; HepG2 cells; wingless/int-3A; nuclear factor (erythroid-derived 2)-like 2; reactive oxygen species; radiation; radiosensitivity
类别
资金
- National Natural Science Foundation of China [31670859, 81470098]
- Natural Science Foundation of Tianjin [15KPXM01SF056]
- Fundamental Research Funds from CAMS and PUMC [2016ZX310068]
- Research Funds for the Innovation Team of IRM-CAMS [1650]
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-3 beta 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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