title: Interleukin-6 counteracts therapy-induced cellular oxidative stress in multiple myeloma by up-regulating manganese superoxide dismutase.
abstract: IL (interleukin)-6, an established growth factor for multiple myeloma cells, induces myeloma therapy resistance, but the resistance mechanisms remain unclear. The present study determines the role of IL-6 in re-establishing intracellular redox homoeostasis in the context of myeloma therapy. IL-6 treatment increased myeloma cell resistance to agents that induce oxidative stress, including IR (ionizing radiation) and Dex (dexamethasone). Relative to IR alone, myeloma cells treated with IL-6 plus IR demonstrated reduced annexin/propidium iodide staining, caspase 3 activation, PARP [poly(ADP-ribose) polymerase] cleavage and mitochondrial membrane depolarization with increased clonogenic survival. IL-6 combined with IR or Dex increased early intracellular pro-oxidant levels that were causally related to activation of NF-κB (nuclear factor κB) as determined by the ability of N-acetylcysteine to suppress both pro-oxidant levels and NF-κB activation. In myeloma cells, upon combination with hydrogen peroxide treatment, relative to TNF (tumour necrosis factor)-α, IL-6 induced an early perturbation in reduced glutathione level and increased NF-κB-dependent MnSOD (manganese superoxide dismutase) expression. Furthermore, knockdown of MnSOD suppressed the IL-6-induced myeloma cell resistance to radiation. MitoSOX Red staining showed that IL-6 treatment attenuated late mitochondrial oxidant production in irradiated myeloma cells. The present study provides evidence that increases in MnSOD expression mediate IL-6-induced resistance to Dex and radiation in myeloma cells. The results of the present study indicate that inhibition of antioxidant pathways could enhance myeloma cell responses to radiotherapy and/or chemotherapy.
authors.affiliation: Free Radical and Radiation Biology Program, Department of Radiation Oncology, University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Charles O
authors.initials: CO
authors.lastname: Brown
authors.forename: Kelley
authors.initials: K
authors.lastname: Salem
authors.forename: Brett A
authors.initials: BA
authors.lastname: Wagner
authors.forename: Soumen
authors.initials: S
authors.lastname: Bera
authors.forename: Neeraj
authors.initials: N
authors.lastname: Singh
authors.forename: Ajit
authors.initials: A
authors.lastname: Tiwari
authors.forename: Amit
authors.initials: A
authors.lastname: Choudhury
authors.forename: Garry R
authors.initials: GR
authors.lastname: Buettner
authors.forename: Apollina
authors.initials: A
authors.lastname: Goel
mesh_terms: D002460:Cell Line; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D006801:Humans; D015850:Interleukin-6 / Q000502:physiology*; D009101:Multiple Myeloma / Q000188:drug therapy / Q000201:enzymology* / Q000628:therapy*; D018384:Oxidative Stress / Q000502:physiology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D013482:Superoxide Dismutase / Q000096:biosynthesis*; D015854:Up-Regulation / Q000502:physiology*
chemical_list: D015850:Interleukin-6; D017382:Reactive Oxygen Species; D013482:Superoxide Dismutase