Department of Laboratory, Zhecheng County People's Hospital of Henan Province, Shangqiu Henan, 476200, China.
Capital Medical University Affiliated Beijing You An Hospital, Beijing, 100069, China; Beijing Institute of Hepatology, Beijing, 100069, China.
Biochem Biophys Res Commun. 2019 Feb 5;509(2):535-540. doi: 10.1016/j.bbrc.2018.12.102. Epub 2018 Dec 28.
AZD3759 is a tyrosine kinase inhibitor and has an encouraging future in treating brain metastases of non-small cell lung cancer. Here, we determined that AZD3759 suppressed the viability of HepG2 cells, a hepatoma cell line, and induced their apoptosis, suggesting a new therapeutic potential of AZD3759 in hepatocellular carcinoma (HCC) treatment. Furthermore, we found that the activation of p53-SMAD family member 4 (SMAD4) positive feedback loop was involved in the induction of bulks of apoptosis in HepG2 cells in response to AZD3759 treatment. In this positive feedback loop, p53 induced the expression of SMAD4 by directly promoting its transcription as shown by p53 could bind to SMAD4 promoter; SMAD4, in turn, promoted the nuclear translocation of p53, which increased the transcription of pro-apoptotic genes, including PUMA and BAX (two p53 target genes) and finally resulted in apoptosis. To the best of our knowledge, p53-induced SMAD4 transcription and SMAD4-determined the sub-location of p53 have not been reported. Taken together, our results demonstrated that AZD3759 might be an alternative strategy for HCC treatment and activating p53-SMAD4 positive feedback loop might enhance its therapeutic effects on HCC.
AZD3759 是一种酪氨酸激酶抑制剂，在治疗非小细胞肺癌脑转移方面具有广阔的应用前景。在这里，我们发现 AZD3759 能够抑制肝癌细胞系 HepG2 细胞的活力并诱导其凋亡，这提示 AZD3759 可能具有治疗肝细胞癌（HCC）的新潜力。此外，我们发现 p53-SMAD 家族成员 4（SMAD4）正反馈环的激活参与了 AZD3759 诱导 HepG2 细胞大量凋亡的过程。在这个正反馈环中，p53 通过直接促进其转录来诱导 SMAD4 的表达，这一点通过 p53 可以结合到 SMAD4 启动子上得以证明；SMAD4 反过来又促进了 p53 的核易位，从而增加了促凋亡基因（包括 PUMA 和 BAX（p53 的两个靶基因）的转录，最终导致细胞凋亡。据我们所知，p53 诱导的 SMAD4 转录和 SMAD4 决定 p53 的亚定位尚未见报道。总之，我们的研究结果表明，AZD3759 可能是治疗 HCC 的一种替代策略，激活 p53-SMAD4 正反馈环可能增强其对 HCC 的治疗效果。
