期刊
BIOCHEMICAL JOURNAL
卷 444, 期 -, 页码 515-527出版社
PORTLAND PRESS LTD
DOI: 10.1042/BJ20112019
关键词
dexamethasone; interleukin-6; manganese superoxide dismutase (MnSOD); multiple myeloma; nuclear factor kappa B (NF-kappa B); radiation therapy.
资金
- National Institutes of Health [CA127958, P30CA086862, T32CA078586, HL089599, GM073929]
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-kappa B (nuclear factor kappa B) as determined by the ability of N-acetylcysteine to suppress both pro-oxidant levels and NF-kappa B activation. In myeloma cells, upon combination with hydrogen peroxide treatment, relative to TNF (tumour necrosis factor)-alpha, IL-6 induced an early perturbation in reduced glutthione level and increased NF-kappa B-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.
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