Enforced expression of superoxide dismutase 2/manganese superoxide dismutase disrupts autocrine interleukin-6 stimulation in human multiple myeloma cells and enhances dexamethasone-induced apoptosis.
Autocrine pathways of proliferative and anti-apoptotic growth factors represent a serious impediment to the treatment of many types of tumors. In particular, interleukin-6 (IL-6), a pleiotropic cytokine known to play a critical role in the survival and growth of multiple myeloma cells, participates in an autocrine stimulation loop that serves to inhibit the induction of apoptosis during chemotherapy. Manganese superoxide dismutase (MnSOD) is an important antioxidant enzyme encoded by the SOD2 gene that attenuates oxidative free radicals in the mitochondria by catalyzing the formation of hydrogen peroxide from superoxide radicals. Transcription factor activity and binding is influenced by the oxidative state of cells, and dysregulation of MnSOD levels can result in abnormal patterns of gene expression. In the human multiple myeloma cell line IM-9, an autocrine IL-6 loop exists, which enables the cell to resist the effects of dexamethasone, a common treatment for multiple myeloma. Here, we show that SOD2 expression is epigenetically silenced in IM-9 cells, and replacement of MnSOD reduces cell proliferation and partially restores susceptibility to dexamethasone. The restoration of MnSOD also serves to decrease the expression levels of IL-6 by reducing the ability of activator protein-1, an important mediator of IL-6 expression in multiple myeloma cells, to bind to its enhancer site. These results show the importance of free radical-mediated dysregulation of autocrine growth factor loops in tumor cells and their effect on cell growth and response to chemotherapy.
Hodge
David R
DR
Laboratory of Molecular Immunoregulation, Cytokine Molecular Mechanisms Section, Center for Cancer Research, National Cancer Institute at Frederick, Maryland, USA. hodje@mail.ncifcrf.gov
Xiao
Weihua
W
Peng
Benjamin
B
Cherry
James C
JC
Munroe
David J
DJ
Farrar
William L
WL
D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D001483:Base Sequence; D045744:Cell Line, Tumor; D019175:DNA Methylation; D003907:Dexamethasone / Q000494:pharmacology*; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis / Q000235:genetics; D008969:Molecular Sequence Data; D009101:Multiple Myeloma / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D013482:Superoxide Dismutase / Q000096:biosynthesis* / Q000235:genetics; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D014162:Transfection; D000099156:Superoxide Dismutase 2; D000093242:Interleukin-6 Inhibitors
D003907:Dexamethasone; D015850:Interleukin-6; D013482:Superoxide Dismutase; D018808:Transcription Factor AP-1; D000099156:Superoxide Dismutase 2; D000093242:Interleukin-6 Inhibitors