Inhibition of hypoxia-inducible factor-1 function enhances the sensitivity of multiple myeloma cells to melphalan
Inhibition of hypoxia-inducible factor-1 function enhances the sensitivity of multiple myeloma cells to melphalan
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DOI：
10.1158/1535-7163.mct-09-0150
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发表时间：
2009-08-01
影响因子：
5.7
通讯作者：
Komatsu, Norio
中科院分区：
文献类型：
--
作者：
Hu, Yongzhen;Kirito, Keita;Komatsu, Norio
低氧诱导因子-1(HIF-1)是细胞对低氧适应最重要的转录因子之一，常见于多种实体肿瘤中。调控失调可诱导肿瘤血管生成，增强肿瘤细胞中抗凋亡蛋白和糖酵解相关酶的表达，进而促进肿瘤生长。在本研究中，我们研究了HIF-1在多发性骨髓瘤中的病理生理作用。此外，我们还探讨了HIF-1可能成为骨髓瘤治疗的分子靶点的可能性。我们鉴定了低氧诱导因子-1α(HIF-1α)亚单位在已建立的骨髓瘤细胞系和原代骨髓瘤细胞中的组成性表达。胰岛素样生长因子-1(IGF-1)通过激活AKT和丝裂原活化蛋白激酶信号通路显著增加HIF-1α的表达。用HIF-1特异性抑制剂棘霉素或针对HIF-1α的siRNA抑制HIF-1功能可增强骨髓瘤细胞对马法兰的敏感性。这种对HIF-1的抑制也逆转了IGF-1对马法兰诱导的细胞凋亡的保护作用。抑制HIF-1显著降低基础和IGF-1诱导的骨髓瘤细胞中最重要的抗凋亡蛋白之一Survivin的表达。我们得出结论，抑制HIF-1可能是多发性骨髓瘤的一种有吸引力的治疗策略。[《摩尔癌症》2009；8(8)：2329-38]
Abnormal activation of hypoxia-inducible factor-1 (HIF-1), one of the most important transcription factors for the adaptation of cells to hypoxia, is frequently observed in numerous types of solid tumors. Dysregulation of induces tumor angiogenesis and enhances the expression of anti-apoptotic proteins and glycolysis-assocated enzymes in cancer cells, which in turn leads to the promotion of tumor growth. In the present study, we examined the pathophysiologic role of HIF-1 in multiple myeloma. Furthermore, we explored the possibility that HIF-1 may be a molecular target for myeloma therapy. We identified constitutive expression of the hypoxia-inducible factor-1 alpha (HIF-1 alpha)-subunit in established myeloma cell lines and in primary myeloma cells. Treatment with insulin-like growth factor-1 (IGF-1) significantly increased HIF-1 alpha expression through activation of the AKT and mitogen-activated protein kinase signaling pathways. Inhibition of HIF-1 function either by echinomycin, a specific HIF-1 inhibitor, or a siRNA against HIF-1 alpha resulted in enhanced sensitivity to melphalan in myeloma cells. This inhibition of HIF-1 also reversed the protective effect of IGF-1 on melphalan-induced apoptosis. Inhibition of HIF-1 drastically reduced both basal and IGF-1-induced expression of survivin, one of the most important anti-apoptotic proteins in myeloma cells. We conclude that HIF-1 inhibition may be an attractive therapeutic strategy for multiple myeloma. [Mol Cancer Their 2009;8(8):2329-38]