Riluzole-induced apoptosis in osteosarcoma is mediated through Yes-associated protein upon phosphorylation by c-Abl Kinase.
Riluzole-induced apoptosis in osteosarcoma is mediated through Yes-associated protein upon phosphorylation by c-Abl Kinase.
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DOI：
10.1038/s41598-021-00439-8
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发表时间：
2021-10-25
影响因子：
4.6
通讯作者：
Mahajan SS
中科院分区：
文献类型：
--
作者：
Raghubir M;Azeem SM;Hasnat R;Rahman CN;Wong L;Yan S;Huang YQ;Zhagui R;Blyufer A;Tariq I;Tam C;Lhamo S;Cecilio L;Chowdhury Y;ChandThakuri S;Mahajan SS
我们实验室先前已经证明阿曲唑是一种有效的抑制人和小鼠骨肉瘤增殖和诱导凋亡的药物。Yes相关蛋白是一种转录辅激活因子，已知其依赖于其蛋白伴侣参与细胞增殖或凋亡。本研究探讨雅普在骨肉瘤细胞凋亡中的作用，推测雅普可能被阿曲唑激活而诱导骨肉瘤细胞凋亡。通过敲低雅普的表达，我们证明了阿曲唑不能诱导雅普缺陷型骨肉瘤细胞凋亡。阿曲唑引起雅普从细胞质易位到细胞核，表明雅普在细胞凋亡中的作用。c-Abl激酶抑制剂可阻断阿珠唑诱导的雅普酪氨酸357位磷酸化和阿珠唑诱导的细胞凋亡。此外，c-Abl激酶的敲低阻止了阿曲唑诱导的LM 7细胞凋亡。我们进一步证明，利鲁唑促进了雅普和p73之间的相互作用，而c-Abl激酶抑制剂则消除了这种相互作用。随后，我们证明了阿曲唑在荧光素酶报告基因测定中增强了Bax启动子的活性，并在ChIP测定中增强了内源性Bax启动子上的雅普/p73结合。我们的数据支持一种新的机制，其中阿曲唑激活c-Abl激酶，调节骨肉瘤中雅普的促凋亡活性。
Our lab has previously demonstrated Riluzole to be an effective drug in inhibiting proliferation and inducing apoptosis in both human and mouse osteosarcoma. Yes-associated protein is a transcription co-activator, known to be involved in cell proliferation or apoptosis depending on its protein partner. In the present study we investigated the role of YAP in apoptosis in osteosarcoma, we hypothesized that YAP may be activated by Riluzole to induce apoptosis in osteosarcoma. By knocking down the expression of YAP, we have demonstrated that Riluzole failed to induce apoptosis in YAP deficient osteosarcoma cells. Riluzole caused translocation of YAP from the cytoplasm to the nucleus, indicating YAP’s role in apoptosis. Both Riluzole-induced phosphorylation of YAP at tyrosine 357 and Riluzole-induced apoptosis were blocked by inhibitors of c-Abl kinase. In addition, knockdown of c-Abl kinase prevented Riluzole-induced apoptosis in LM7 cells. We further demonstrated that Riluzole promoted interaction between YAP and p73, while c-Abl kinase inhibitors abolished the interaction. Subsequently, we demonstrated that Riluzole enhanced activity of the Bax promoter in a luciferase reporter assay and enhanced YAP/p73 binding on endogenous Bax promoter in a ChIP assay. Our data supports a novel mechanism in which Riluzole activates c-Abl kinase to regulate pro-apoptotic activity of YAP in osteosarcoma.
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影响因子：
3.7
作者：
Liao S;Ruiz Y;Gulzar H;Yelskaya Z;Ait Taouit L;Houssou M;Jaikaran T;Schvarts Y;Kozlitina K;Basu-Roy U;Mansukhani A;Mahajan SS
通讯作者：
Mahajan SS
影响因子：
64.5
作者：
Dong, Jixin;Feldmann, Georg;Pan, Duojia
通讯作者：
Pan, Duojia
影响因子：
16
作者：
Basu, S;Totty, NF;Downward, J
通讯作者：
Downward, J
影响因子：
6
作者：
Liu J;Wang LN
通讯作者：
Wang LN
影响因子：
9.9
作者：
Doble, A
通讯作者：
Doble, A