Yang Minghua, Zeng Pei, Kang Rui, Yu Yan, Yang Liangchun, Tang Daolin, Cao Lizhi
Department of Pediatrics, Xiangya Hospital, Central South University, Changsha Hunan, China.
Department of Surgery, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania, United States of America.
PLoS One. 2014 May 12;9(5):e97242. doi: 10.1371/journal.pone.0097242. eCollection 2014.
Autophagy is a double-edged sword in tumorigenesis and plays an important role in the resistance of cancer cells to chemotherapy. S100A8 is a member of the S100 calcium-binding protein family and plays an important role in the drug resistance of leukemia cells, with the mechanisms largely unknown. Here we report that S100A8 contributes to drug resistance in leukemia by promoting autophagy. S100A8 level was elevated in drug resistance leukemia cell lines relative to the nondrug resistant cell lines. Adriamycin and vincristine increased S100A8 in human leukemia cells, accompanied with upregulation of autophagy. RNA interference-mediated knockdown of S100A8 restored the chemosensitivity of leukemia cells, while overexpression of S100A8 enhanced drug resistance and increased autophagy. S100A8 physically interacted with the autophagy regulator BECN1 and was required for the formation of the BECN1-PI3KC3 complex. In addition, interaction between S100A8 and BECN1 relied upon the autophagic complex ULK1-mAtg13. Furthermore, we discovered that exogenous S100A8 induced autophagy, and RAGE was involved in exogenous S100A8-regulated autophagy. Our data demonstrated that S100A8 is involved in the development of chemoresistance in leukemia cells by regulating autophagy, and suggest that S100A8 may be a novel target for improving leukemia therapy.
自噬在肿瘤发生过程中是一把双刃剑，在癌细胞对化疗的耐药性中起重要作用。S100A8是S100钙结合蛋白家族的成员，在白血病细胞的耐药性中起重要作用，但其机制 largely unknown。在此我们报道，S100A8通过促进自噬导致白血病耐药。相对于非耐药细胞系，耐药白血病细胞系中S100A8水平升高。阿霉素和长春新碱可增加人白血病细胞中的S100A8，并伴有自噬上调。RNA干扰介导的S100A8敲低恢复了白血病细胞的化学敏感性，而S100A8的过表达增强了耐药性并增加了自噬。S100A8与自噬调节因子BECN1发生物理相互作用，是BECN1-PI3KC3复合物形成所必需的。此外，S100A8与BECN1之间的相互作用依赖于自噬复合物ULK1-mAtg13。此外，我们发现外源性S100A8诱导自噬，且RAGE参与外源性S100A8调节的自噬。我们的数据表明，S100A8通过调节自噬参与白血病细胞化疗耐药的发生，并提示S100A8可能是改善白血病治疗的新靶点。
