机构：[1]The Center of Diagnosis and Treatment for Children’s Bone Diseases, The Children’s Hospital Affiliated to Soochow University, Suzhou, China[2]The Department of Orthopedics, The Second Affiliated Hospital of Soochow University, Suzhou, China[3]Department of Orthopedics, The Affiliated Jiangyin Hospital of Medical College of Southeast University, Jiangyin, China
Malignant osteosarcoma (OS) is still a deadly disease for many affected patients. The search for the novel anti-OS agent is extremely urgent and important. Our previous study has proposed that salinomycin is a novel anti-OS agent. Here we characterized DNA-dependent protein kinase catalytic subunit (DNA-PKcs) as a primary salinomycin resistance factor in OS cells. DNA-PKcs inhibitors (NU7026, NU7441 and LY294002) or DNA-PKcs shRNA knockdown dramatically potentiated salinomycin-induced death and apoptosis of OS cells (U2OS and MG-63 lines). Further, forced-expression of microRNA-101 ("miR-101") downregulated DNA-PKcs and augmented salinomycin's cytotoxicity against OS cells. Reversely, over-expression of DNA-PKcs in OS cells inhibited salinomycin's lethality. For the mechanism study, we show that DNA-PKcs is required for salinomycin-induced pro-survival autophagy activation. DNA-PKcs inhibition (by NU7441), shRNA knockdown or miR-101 expression inhibited salinomycin-induced Beclin-1 expression and autophagy induction. Meanwhile, knockdown of Beclin-1 by shRNA significantly sensitized salinomycin-induced OS cell lethality. In vivo, salinomycin administration suppressed U2OS xenograft tumor growth in severe combined immuno-deficient (SCID) mice, and its anti-tumor activity was dramatically potentiated with co-administration of the DNA-PKcs inhibitor NU7026. Together, these results suggest that DNA-PKcs could be a primary resistance factor of salinomycin in OS cells. DNA-PKcs inhibition or silence may thus significantly increase salinomycin's sensitivity in OS cells.
基金：
The study was supported by the nature science foundation of China (81171712 and 81402475). Grants from Natural Science Foundation of Jiangsu Province (BK20151213) and Innovation Project of JiangSu Province (201423).
第一作者机构：[1]The Center of Diagnosis and Treatment for Children’s Bone Diseases, The Children’s Hospital Affiliated to Soochow University, Suzhou, China
共同第一作者：
通讯作者：
通讯机构：[1]The Center of Diagnosis and Treatment for Children’s Bone Diseases, The Children’s Hospital Affiliated to Soochow University, Suzhou, China[2]The Department of Orthopedics, The Second Affiliated Hospital of Soochow University, Suzhou, China
推荐引用方式(GB/T 7714)：
Yun-fang Zhen,Song-tao Li,Yun-rong Zhu,et al.Identification of DNA-PKcs as a primary resistance factor of salinomycin in osteosarcoma cells[J].ONCOTARGET.2016,7(48):79417-79427.doi:10.18632/oncotarget.12712.
APA：
Yun-fang Zhen,Song-tao Li,Yun-rong Zhu,Xiao-dong Wang,Xiao-zhong Zhou&Lun-qing Zhu.(2016).Identification of DNA-PKcs as a primary resistance factor of salinomycin in osteosarcoma cells.ONCOTARGET,7,(48)
MLA：
Yun-fang Zhen,et al."Identification of DNA-PKcs as a primary resistance factor of salinomycin in osteosarcoma cells".ONCOTARGET 7..48(2016):79417-79427
医学