PT  - JOURNAL ARTICLE
AU  - Hu, Yongzhen
AU  - Kirito, Keita
AU  - Yoshida, Kozue
AU  - Mitsumori, Toru
AU  - Nakajima, Kei
AU  - Nozaki, Yumi
AU  - Hamanaka, Satoshi
AU  - Nagashima, Takahiro
AU  - Kunitama, Masae
AU  - Sakoe, Kumi
AU  - Komatsu, Norio
TI  - Inhibition of hypoxia-inducible factor-1 function enhances the sensitivity of multiple myeloma cells to melphalan
AID  - 10.1158/1535-7163.MCT-09-0150
DP  - 2009 Aug 01
TA  - Molecular Cancer Therapeutics
PG  - 2329--2338
VI  - 8
IP  - 8
4099  - http://mct.aacrjournals.org/content/8/8/2329.short
4100  - http://mct.aacrjournals.org/content/8/8/2329.full
SO  - Mol Cancer Ther2009 Aug 01; 8
AB  - 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 HIF-1 induces tumor angiogenesis and enhances the expression of anti-apoptotic proteins and glycolysis-associated 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 α (HIF-1α)-subunit in established myeloma cell lines and in primary myeloma cells. Treatment with insulin-like growth factor-1 (IGF-1) significantly increased HIF-1α 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-1α 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 Ther 2009;8(8):2329–38]