title: Potential crosstalk of the interleukin-6-heme oxygenase-1-dependent mechanism involved in resistance to lenalidomide in multiple myeloma cells.
abstract: Interleukin (IL)-6 is one of the most important survival factors in multiple myeloma (MM), and determines the poor prognosis of MM. IL-6 mainly has a paracrine bone marrow stromal cell origin and an autocrine MM cell origin. As an enzyme having cytoprotective effects, heme oxygenase-1 (HO-1) promotes the growth and drug resistance of various malignant tumors. HO-1 expression levels in bone marrow CD138(+) cells of MM patients were significantly higher than those in healthy donors, and positively correlated with both serum IL-6 and intracellular IL-6 mRNA expression levels. Culture of U266, RPMI8226 and CD138(+) cells with exogenous IL-6 in vitro induced high HO-1 expression levels and allowed them to resist lenalidomide. It is hypothesized that this was probably attributable to IL-6-mediated activation of the Janus kinase 2-signal transducer and activator of transcription 3 pathway. In contrast, without IL-6 coculture, enhanced HO-1 expression in U266, RPMI8226 and bone marrow CD138(+) cells from MM patients significantly inreased IL-6 mRNA expression levels and facilitated autocrine IL-6 production. The findings were associated with high HO-1 expression-enhanced p38 mitogen-activated protein kinase phosphorylation. Reduced HO-1 expression sensitized MM cells to lenalidomide. Therefore, we postulated that IL-6 in the bone marrow microenvironment of MM patients stimulated high HO-1 expression in MM cells and their resistance to lenalidomide. High HO-1 expression also stimulated autocrine IL-6 production, and exacerbated drug resistance and disease. This study supports the use of HO-1 as a possible marker for both MM prognosis and drug resistance, and as a potential therapeutic target.
authors.affiliation: Department of Hematology, Affiliated Hospital of Guizhou Medical University, Guiyang, China.|Key Laboratory of Hematological Disease Diagnostic & Treat Centre of GuiZhou Province, Guiyang, China.|GuiZhou Province Hematopoietic Stem Cell Transplantation Center, Affiliated Hospital of Guizhou Medical University, Guiyang, China.
authors.forename: Weibing
authors.initials: W
authors.lastname: Wu
authors.affiliation: Department of Hematology, Affiliated Hospital of Guizhou Medical University, Guiyang, China.|Department of Pharmacy, Affiliated BaiYun Hospital of Guizhou Medical University, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Ma
authors.affiliation: Department of Hematology, Affiliated Hospital of Guizhou Medical University, Guiyang, China.|Key Laboratory of Hematological Disease Diagnostic & Treat Centre of GuiZhou Province, Guiyang, China.|GuiZhou Province Hematopoietic Stem Cell Transplantation Center, Affiliated Hospital of Guizhou Medical University, Guiyang, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Wang
authors.affiliation: School of Pharmacy, Guizhou Medical University, Guiyang, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Cao
authors.affiliation: School of Pharmacy, Guizhou Medical University, Guiyang, China.
authors.forename: Tangsheng
authors.initials: T
authors.lastname: Lu
authors.affiliation: Department of Hematology, Affiliated Hospital of Guizhou Medical University, Guiyang, China.|Department of Pharmacy, Affiliated BaiYun Hospital of Guizhou Medical University, China.|Department of Pharmacy, Affiliated Hospital of Guizhou Medical University, Guiyang, China.
authors.forename: Qin
authors.initials: Q
authors.lastname: Fang
authors.affiliation: Department of Hematology, Affiliated Hospital of Guizhou Medical University, Guiyang, China.|Key Laboratory of Hematological Disease Diagnostic & Treat Centre of GuiZhou Province, Guiyang, China.|GuiZhou Province Hematopoietic Stem Cell Transplantation Center, Affiliated Hospital of Guizhou Medical University, Guiyang, China.
authors.forename: Jiangyuan
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Department of Hematology, Affiliated Hospital of Guizhou Medical University, Guiyang, China.|Key Laboratory of Hematological Disease Diagnostic & Treat Centre of GuiZhou Province, Guiyang, China.|GuiZhou Province Hematopoietic Stem Cell Transplantation Center, Affiliated Hospital of Guizhou Medical University, Guiyang, China.
authors.forename: Jishi
authors.initials: J
authors.lastname: Wang
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D002460:Cell Line; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D019008:Drug Resistance, Neoplasm; D005260:Female; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism*; D053614:Janus Kinase 2 / Q000378:metabolism; D000077269:Lenalidomide; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000378:metabolism*; D010766:Phosphorylation; D050796:STAT3 Transcription Factor / Q000378:metabolism; D053668:Syndecan-1 / Q000378:metabolism; D013792:Thalidomide / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; C508600:IL6 protein, human; D015850:Interleukin-6; C508241:SDC1 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D053668:Syndecan-1; D013792:Thalidomide; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1; C507924:JAK2 protein, human; D053614:Janus Kinase 2; D000077269:Lenalidomide
keywords: JAK2-STAT3; heme oxygenase-1; interleukin-6; multiple myeloma; p38 mitogen-activated protein kinase