title: Phosphorylation of apoptosis repressor with caspase recruitment domain by protein kinase CK2 contributes to chemotherapy resistance by inhibiting doxorubicin induced apoptosis.
abstract: 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.
authors.affiliation: Institute for Translational Medicine, Medical College of Qingdao University, Qingdao, 266021, China.
authors.forename: Jianxun
authors.initials: J
authors.lastname: Wang
authors.affiliation: National Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China.
authors.forename: Chang
authors.initials: C
authors.lastname: Feng
authors.affiliation: Department of Gastroenterology, Beijing Military General Hospital, Beijing, 100700, China.
authors.forename: Yuqi
authors.initials: Y
authors.lastname: He
authors.affiliation: Affiliated Hospital, Medical College of Qingdao University, Qingdao, 266003, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Ding
authors.affiliation: Department of Gastroenterology, Beijing Military General Hospital, Beijing, 100700, China.
authors.forename: Jianqiu
authors.initials: J
authors.lastname: Sheng
authors.affiliation: National Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Arshad
authors.affiliation: National Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China.
authors.forename: Xiaojie
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Institute for Translational Medicine, Medical College of Qingdao University, Qingdao, 266021, China.
authors.forename: Peifeng
authors.initials: P
authors.lastname: Li
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry; D017209:Apoptosis; D047390:Casein Kinase II / Q000378:metabolism; D020169:Caspases / Q000378:metabolism*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D002470:Cell Survival; D003598:Cytoskeletal Proteins / Q000378:metabolism; D004317:Doxorubicin / Q000737:chemistry*; D019008:Drug Resistance, Neoplasm; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008928:Mitochondria / Q000378:metabolism; D009368:Neoplasm Transplantation; D009419:Nerve Tissue Proteins / Q000378:metabolism; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D013274:Stomach Neoplasms / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D003598:Cytoskeletal Proteins; D009419:Nerve Tissue Proteins; C092069:activity regulated cytoskeletal-associated protein; D004317:Doxorubicin; C570325:CSNK2A1 protein, human; D047390:Casein Kinase II; D020169:Caspases
keywords: ARC; CK2; apoptosis; chemotherapy resistance; doxorubicin