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Enforced Expression of Superoxide Dismutase 2/Manganese Superoxide Dismutase Disrupts Autocrine Interleukin-6 Stimulation in Human Multiple Myeloma Cells and Enhances Dexamethasone-Induced Apoptosis

¹ Laboratory of Molecular Immunoregulation, Cytokine Molecular Mechanisms Section, Center for Cancer Research and ² Laboratory of Molecular Technology, National Cancer Institute at Frederick and ³ Intramural Research Support Program-Basic Research Program, Science Applications International Corp.-Frederick, Frederick, Maryland

Requests for reprints: David R. Hodge, Laboratory of Molecular Immunoregulation, National Cancer Institute at Frederick, 1050 Boyles Street, Building 560, Room 31-76, Frederick, MD. Phone: 301-846-6865; E-mail: hodje{at}mail.ncifcrf.gov.

Autocrine pathways of proliferative and antiapoptotic 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.

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