华蟾素诱导ENKUR增加p53稳定性逆转Snail介导的EMT信号抑制肺腺癌继发性顺铂耐药

肺腺癌顺铂（DDP）继发性耐药分子基础一直有待明确。前期我们发现间质纤维化表型转变是肺腺癌DDP继发性耐药的关键事件之一。机制研究初步显示，DDP通过激活PI3K/AKT/c-Jun信号下调ENKUR以及诱导上皮间质转化（EMT）通路。ENKUR作为新的抑癌候选基因，能与p85结合，抑制PI3K/AKT/c-Jun信号和泛素表达，增加p53表达以及失活Snail介导的EMT信号。有意思的是，我们新获得的华蟾素化合物在DDP耐药肺腺癌细胞中明显诱导ENKUR表达。后续研究明确：华蟾素通过抑制PI3K/AKT/c-Jun上调ENKUR，后者与p85结合，抑制PI3K/AKT/c-Jun信号，下调泛素表达，降低p53泛素化降解，最终抑制Snail介导的EMT信号，从而逆转DDP肺腺癌继发性耐药。本研究揭示华蟾素诱导ENKUR逆转肺腺癌DDP耐药作用机理，这为其临床应用奠定新的实验基础。

The molecular basis underlying secondary resistance of cisplatin(DDP) in lung adenocarcinoma remains to be clarified. In the prior study, we found that the phenotype transformation of interstitial fibrosis was a key event during constructing DDP-resistant lung adenocarcinoma cell line. Preliminary mechanism studies indicated that decreased expression of ENKUR and activation of EMT signaling were observed in DDP-resistant cell line. ENKUR as a new tumor suppressor could bind to p85, suppress the expression of PI3K/AKT/c-Jun and Ubiquitin, increase p53 expression and inactivate EMT signal. Interestingly, we found that new chemical compound bufotoxin significantly increased expression of ENKUR. In the further investigation, we will confirm that bufotoxin suppresses PI3K/AKT/c-Jun signal and thus upregulates ENKUR expression. The latter will directly bind to p85 protein and therefore reduce PI3K/AKT/c-Jun signal, which therefore decreases the expression of Ubiquitin and further attenuates p53 ubiquitination degradation. Increased p53 protein finally suppresses Snail-induced EMT signal and reverses secondary resistance of DDP in lung adenocarcinoma. Our study will reveal the action and molecular basis of bufotoxin in reversing DDP resistance by inducing ENKUR in lung adenocarcinoma, which may lay an experimental foundation for clinical application of bufotoxin.