Phosphorylation of apoptosis repressor with caspase recruitment domain by protein kinase CK2 contributes to chemotherapy resistance by inhibiting doxorubicin induced apoptosis
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Jianxun Wang1,*, Chang Feng2,*, Yuqi He3,*, Wei Ding4, Jianqiu Sheng3, Muhammad Arshad2, Xiaojie Zhang2, Peifeng Li1
1Institute for Translational Medicine, Medical College of Qingdao University, Qingdao, 266021, China
2National Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China
3Department of Gastroenterology, Beijing Military General Hospital, Beijing, 100700, China
4Affiliated Hospital, Medical College of Qingdao University, Qingdao, 266003, China
*These authors have contributed equally to this work
Peifeng Li, e-mail: [email protected]
Jianxun Wang, e-mail: [email protected]
Keywords: chemotherapy resistance, ARC, CK2, apoptosis, doxorubicin
Received: February 05, 2015 Accepted: June 17, 2015 Published: June 27, 2015
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.
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