Enforced expression of superoxide dismutase 2/manganese superoxide dismutase disrupts autocrine interleukin-6 stimulation in human multiple myeloma cells and enhances dexamethasone-induced apoptosis
Enforced expression of superoxide dismutase 2/manganese superoxide dismutase disrupts autocrine interleukin-6 stimulation in human multiple myeloma cells and enhances dexamethasone-induced apoptosis
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DOI：
10.1158/0008-5472.can-04-4482
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发表时间：
2005-07-15
期刊：
影响因子：
11.2
通讯作者：
Farrar, WL
中科院分区：
文献类型：
--
作者：
Hodge, DR;Xiao, WH;Farrar, WL
增殖和抗凋亡生长因子的自分泌途径是许多类型肿瘤治疗的严重障碍。尤其是白介素6(IL-6)，一种已知在多发性骨髓瘤细胞生存和生长中起关键作用的多效性细胞因子，参与自分泌。在化疗过程中抑制细胞凋亡诱导的刺激环路。锰超氧化物歧化酶(MnSOD)是由SOD2基因编码的一种重要的抗氧化酶，它通过催化超氧自由基生成过氧化氢来减弱线粒体中的氧化自由基。转录因子的活性和结合受到细胞氧化状态的影响，而MnSOD水平的失调可能导致基因表达的异常模式。在人类多发性骨髓瘤细胞系IM-9中，存在一个自分泌的IL-6环，使该细胞能够抵抗地塞米松的影响，地塞米松是多发性骨髓瘤的常见治疗方法。在这里，我们表明，在IM-9细胞中，SOD2的表达在表观遗传上是沉默的，并且MnSOD的替代减少了细胞的增殖，并部分恢复了对地塞米松的敏感性。MnSOD的修复还通过降低多发性骨髓瘤细胞中IL-6表达的重要介质激活蛋白-1与其增强子结合的能力来降低IL-6的表达水平。这些结果表明了自由基介导的肿瘤细胞自分泌生长因子环失调的重要性，以及它们对细胞生长和化疗反应的影响。
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 syperoxide 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.