Benzyl Isothiocyanate potentiates p53 signaling and antitumor effects against breast cancer through activation of p53-LKB1 and p73-LKB1 axes.
Benzyl Isothiocyanate potentiates p53 signaling and antitumor effects against breast cancer through activation of p53-LKB1 and p73-LKB1 axes.
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异硫氰酸苄酯通过激活p53-LKB1和p73-LKB1轴来增强p53信号传导和抗肿瘤效应。
DOI：
10.1038/srep40070
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发表时间：
2017-01-10
影响因子：
4.6
通讯作者：
Sharma D
中科院分区：
文献类型：
--
作者：
Xie B;Nagalingam A;Kuppusamy P;Muniraj N;Langford P;Győrffy B;Saxena NK;Sharma D
由于p53在人类癌症中频繁失活，p53通路的功能性再激活虽然艰巨，但可能为癌症治疗提供广泛的策略。使用磷蛋白筛选阵列，我们发现异硫氰酸苄酯（BITC）增加乳腺癌细胞中的p53磷酸化，并揭示ERK和PRAS 40/MDM 2在BITC介导的p53激活中的重要作用。我们发现，BITC拯救和激活p53信号网络，抑制p53突变细胞的生长。在机制上，BITC诱导p53突变细胞中的p73表达，破坏p73和突变体-p53的相互作用，从而从隔离中释放p73并使其具有转录活性。此外，BITC诱导的p53和p73轴会聚在肿瘤抑制因子LKB 1上，LKB 1在p53野生型和p53突变型细胞中分别被p53和p73转录上调;并且在前馈机制中，LKB 1与p53和p73拴系以募集到p53响应性启动子。使用LKB 1-null细胞对BITC处理的异种移植物的分析证实了体外机制发现，并确立了LKB 1作为BITC增强以及拯救p53-野生型以及p53-突变型细胞中的p53-通路的关键节点。这些数据提供了第一个在体外和体内的证据，以前未被识别的BITC，p53/LKB 1和p73/LKB 1轴之间的串扰在乳腺肿瘤生长抑制的整体作用。
Functional reactivation of p53 pathway, although arduous, can potentially provide a broad-based strategy for cancer therapy owing to frequent p53 inactivation in human cancer. Using a phosphoprotein-screening array, we found that Benzyl Isothiocynate, (BITC) increases p53 phosphorylation in breast cancer cells and reveal an important role of ERK and PRAS40/MDM2 in BITC-mediated p53 activation. We show that BITC rescues and activates p53-signaling network and inhibits growth of p53-mutant cells. Mechanistically, BITC induces p73 expression in p53-mutant cells, disrupts the interaction of p73 and mutant-p53, thereby releasing p73 from sequestration and allowing it to be transcriptionally active. Furthermore, BITC-induced p53 and p73 axes converge on tumor-suppressor LKB1 which is transcriptionally upregulated by p53 and p73 in p53-wild-type and p53-mutant cells respectively; and in a feed-forward mechanism, LKB1 tethers with p53 and p73 to get recruited to p53-responsive promoters. Analyses of BITC-treated xenografts using LKB1-null cells corroborate in vitro mechanistic findings and establish LKB1 as the key node whereby BITC potentiates as well as rescues p53-pathway in p53-wild-type as well as p53-mutant cells. These data provide first in vitro and in vivo evidence of the integral role of previously unrecognized crosstalk between BITC, p53/LKB1 and p73/LKB1 axes in breast tumor growth-inhibition.