Phosphorylation of apoptosis repressor with caspase recruitment domain by protein kinase CK2 contributes to chemotherapy resistance by inhibiting doxorubicin induced apoptosis.
Phosphorylation of apoptosis repressor with caspase recruitment domain by protein kinase CK2 contributes to chemotherapy resistance by inhibiting doxorubicin induced apoptosis.
复制标题
蛋白激酶 CK2 磷酸化具有 caspase 募集结构域的凋亡抑制因子，通过抑制阿霉素诱导的细胞凋亡，从而有助于化疗耐药
DOI：
10.18632/oncotarget.4392
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发表时间：
2015-09-29
期刊：
影响因子：
--
通讯作者：
Li P
中科院分区：
文献类型：
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作者：
Wang J;Feng C;He Y;Ding W;Sheng J;Arshad M;Zhang X;Li P
肿瘤对化疗产生耐药性是肿瘤治疗的主要障碍。在此，我们发现凋亡抑制因子与苏氨酸149位的半胱氨酸天冬氨酸氨基转移酶招募结构域(ARC)的磷酸化对于抑制阿霉素(DOX)诱导的癌细胞的凋亡和线粒体的分裂是必不可少的。我们的进一步研究表明，酪蛋白激酶II(CK2)抑制剂可以降低ARC的磷酸化水平，并使癌细胞对凋亡敏感。此外，DOX还观察到CK2的催化亚基CK2α和CK2α‘移位到癌细胞的核中。最后，在肿瘤移植瘤模型上证实了DOX和CK2抑制剂的协同治疗作用。综上所述，我们的结果表明，CK2介导的ARC的磷酸化通过抑制DOX诱导的细胞凋亡而参与化疗耐药，DOX与CK2抑制剂联合应用可以通过下调ARC的磷酸化而协同诱导癌细胞的凋亡。因此，开发以ARC和CK2为基础的新的治疗策略，有望克服肿瘤对化疗的耐药性。
The development of cancer resistance to chemotherapy is the major obstacle to cancer therapy. Here, we identified that the phosphorylation of apoptosis repressor with caspase recruitment domain (ARC) at threonine 149 was essential to inhibit doxorubicin (DOX) induced apoptosis and mitochondrial fission in cancer cells. Our further study showed that casein kinase II (CK2) inhibitors could decrease the phosphorylation levels of ARC and make cancer cells sensitive to undergoing apoptosis. Furthermore, CK2α and CK2α', catalytic subunits of CK2, were observed to translocate into nuclear in cancer cells with the treatment of DOX. Finally, the synergistically therapeutic effect by combining DOX and CK2 inhibitor was confirmed in tumor xenograft model. Taken together, our results revealed that CK2-mediated phosphorylation of ARC contributed to chemotherapy resistance by inhibiting DOX induced apoptosis and combining DOX with CK2 inhibitor could induce apoptosis of cancer cells synergistically by down-regulating the phosphorylation of ARC. Therefore, development of new therapeutic strategies based on ARC and CK2, is promising for overcoming cancer resistance to chemotherapy.