title: Heme oxygenase-1 contributes to imatinib resistance by promoting autophagy in chronic myeloid leukemia through disrupting the mTOR signaling pathway.
abstract: Heme oxygenase-1 (HO-1) has been verified to play an important role in imatinib (IM)-resistant chronic myeloid leukemia (CML) cells, but the mechanism remains unclear. In drug resistant CML cells, HO-1 expression abnormally increased and that of autophagy-related protein LC-3I/II also increased, so we herein postulated HO-1 was associated with autophagy. HO-1 expressions in IM-sensitive/resistant K562/K562R cells were regulated through lentiviral mediation. K562 cells transfected with HO-1 resisted IM and underwent obvious autophagy. After HO-1 expression was silenced in K562R cells, autophagy was inhibited and the sensitivity to IM was increased. The findings were related with the inhibitory effects of high HO-1 expression on the mTOR signaling pathway that negatively regulated autophagy. High HO-1 expression promoted autophagy by inhibiting mTOR. Similar to the cell line results, mononuclear cells of IM-resistant CML patients became significantly sensitive to IM when HO-1 expression was inhibited. In summary, HO-1, which is involved in the development of chemoresistance in leukemia cells by regulating autophagy, may be a novel target for improving leukemia therapy.
authors.affiliation: School of Pharmacy, Guizhou Medical University, Guiyang 550004, PR China.
authors.forename: Lu
authors.initials: L
authors.lastname: Cao
authors.affiliation: Department of Hematology, Affiliated Hospital of Guizhou Medical University, Guiyang 550004, PR China; Guizhou Province Hematopoietic Stem Cell Transplantation Center, Guiyang 550004, PR China; Key Laboratory of Hematological Disease Diagnostic and Treat Centre of Guizhou Province, Guiyang 550004, PR China; Guizhou Province Hematology Institute, Guiyang 550004, PR China.
authors.forename: Jishi
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Pharmacy, Affiliated Baiyun Hospital of Guizhou Medical University, Guiyang 550058, PR China.
authors.forename: Dan
authors.initials: D
authors.lastname: Ma
authors.affiliation: Department of Hematology, Affiliated Hospital of Guizhou Medical University, Guiyang 550004, PR China; Guizhou Province Hematopoietic Stem Cell Transplantation Center, Guiyang 550004, PR China; Key Laboratory of Hematological Disease Diagnostic and Treat Centre of Guizhou Province, Guiyang 550004, PR China; Guizhou Province Hematology Institute, Guiyang 550004, PR China.
authors.forename: Ping
authors.initials: P
authors.lastname: Wang
authors.affiliation: Department of Hematology, Affiliated Hospital of Guizhou Medical University, Guiyang 550004, PR China; Guizhou Province Hematopoietic Stem Cell Transplantation Center, Guiyang 550004, PR China; Key Laboratory of Hematological Disease Diagnostic and Treat Centre of Guizhou Province, Guiyang 550004, PR China; Guizhou Province Hematology Institute, Guiyang 550004, PR China.
authors.forename: Yaming
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Pharmacy, Affiliated Baiyun Hospital of Guizhou Medical University, Guiyang 550058, PR China; Department of Hematology, Affiliated Hospital of Guizhou Medical University, Guiyang 550004, PR China. Electronic address: fq_fangqin@sina.com.
authors.forename: Qin
authors.initials: Q
authors.lastname: Fang
mesh_terms: D000328:Adult; D000368:Aged; D001343:Autophagy / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D020868:Gene Silencing / Q000187:drug effects; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D006801:Humans; D000068877:Imatinib Mesylate / Q000494:pharmacology / Q000627:therapeutic use*; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D015398:Signal Transduction / Q000187:drug effects*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects; D055815:Young Adult
chemical_list: D000068877:Imatinib Mesylate; D051547:Heme Oxygenase-1; D058570:TOR Serine-Threonine Kinases