title: S100A8 contributes to drug resistance by promoting autophagy in leukemia cells.
abstract: 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.
authors.affiliation: Department of Pediatrics, Xiangya Hospital, Central South University, Changsha Hunan, China.
authors.forename: Minghua
authors.initials: M
authors.lastname: Yang
authors.affiliation: Department of Pediatrics, Xiangya Hospital, Central South University, Changsha Hunan, China.
authors.forename: Pei
authors.initials: P
authors.lastname: Zeng
authors.affiliation: Department of Surgery, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Rui
authors.initials: R
authors.lastname: Kang
authors.affiliation: Department of Pediatrics, Xiangya Hospital, Central South University, Changsha Hunan, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Department of Pediatrics, Xiangya Hospital, Central South University, Changsha Hunan, China.
authors.forename: Liangchun
authors.initials: L
authors.lastname: Yang
authors.affiliation: Department of Infectious Diseases, Xiangya Hospital, Central South University, Changsha, Hunan, China; Department of Surgery, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Daolin
authors.initials: D
authors.lastname: Tang
authors.affiliation: Department of Pediatrics, Xiangya Hospital, Central South University, Changsha Hunan, China.
authors.forename: Lizhi
authors.initials: L
authors.lastname: Cao
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects*; D000071186:Beclin-1; D040501:Calgranulin A / Q000378:metabolism*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007938:Leukemia / Q000473:pathology*; D008565:Membrane Proteins / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; D040501:Calgranulin A; D008565:Membrane Proteins; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D019869:Phosphatidylinositol 3-Kinases