title: S100A8-targeting siRNA enhances arsenic trioxide-induced myeloid leukemia             cell death by down-regulating autophagy.
abstract: Chemoresistance has become a major obstacle to the successful treatment of leukemia. Autophagy, a regulated process of degradation and recycling of cellular constituents, has recently caught increasing attention for its roles in conferring resistance to various commonly used anticancer therapies. Here we showed that the member of the S100 calcium-binding protein family, S100A8, is a critical regulator of chemoresistance in the autophagy process. It positively correlated with the clinical status in childhood acute myeloblastic leukemia (AML) and it was released from leukemia cells after chemotherapy-induced cytotoxicity. Knockdown of S100A8 expression increased the sensitivity of leukemia cells to chemotherapy and apoptosis. Moreover, suppressing S100A8 expression decreased autophagy as evaluated by the increased expression of the autophagic marker microtubule-associated protein light chain 3 (LC3)-II, degradation of SQSTM1/Sequestosome 1 (p62) and formation of autophagosomes. Furthermore, stimuli that enhanced reactive oxygen species (ROS) promoted cytosolic translocation of S100A8 and thereby enhanced autophagy. S100A8 directly interacted with the autophagy protein Beclin1 displacing Bcl-2. These results suggest that S100A8 is a critical pro-autophagic protein that enhances cell survival and regulates chemoresistance in leukemia cells likely through disassociating the Beclin1-Bcl-2 complex.
authors.affiliation: Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, Hunan, PR China.
authors.forename: Liangchun
authors.initials: L
authors.lastname: Yang
authors.forename: Minghua
authors.initials: M
authors.lastname: Yang
authors.forename: Hong
authors.initials: H
authors.lastname: Zhang
authors.forename: Zhuo
authors.initials: Z
authors.lastname: Wang
authors.forename: Yan
authors.initials: Y
authors.lastname: Yu
authors.forename: Min
authors.initials: M
authors.lastname: Xie
authors.forename: Mingyi
authors.initials: M
authors.lastname: Zhao
authors.forename: Liying
authors.initials: L
authors.lastname: Liu
authors.forename: Lizhi
authors.initials: L
authors.lastname: Cao
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D001343:Autophagy / Q000187:drug effects*; D000071186:Beclin-1; D040501:Calgranulin A / Q000235:genetics* / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D004357:Drug Synergism; D005434:Flow Cytometry; D018922:HL-60 Cells; D006801:Humans; D020014:K562 Cells; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D008565:Membrane Proteins / Q000378:metabolism; D010087:Oxides / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D014162:Transfection; D014407:Tumor Cells, Cultured
chemical_list: D051017:Apoptosis Regulatory Proteins; D001152:Arsenicals; C491997:BECN1 protein, human; D000071186:Beclin-1; D040501:Calgranulin A; D008565:Membrane Proteins; D010087:Oxides; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D000077237:Arsenic Trioxide