Inhibition of hypoxia-inducible factor-1 function enhances the sensitivity of multiple myeloma cells to melphalan.
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 alpha (HIF-1alpha)-subunit in established myeloma cell lines and in primary myeloma cells. Treatment with insulin-like growth factor-1 (IGF-1) significantly increased HIF-1alpha 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-1alpha 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.
Hu
Yongzhen
Y
Department of Hematology and Oncology, University of Yamanashi, Yamanashi, Japan.
Kirito
Keita
K
Yoshida
Kozue
K
Mitsumori
Toru
T
Nakajima
Kei
K
Nozaki
Yumi
Y
Hamanaka
Satoshi
S
Nagashima
Takahiro
T
Kunitama
Masae
M
Sakoe
Kumi
K
Komatsu
Norio
N
D018941:Antigens, CD19 / Q000378:metabolism; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D017209:Apoptosis; D045744:Cell Line, Tumor; D004448:Echinomycin / Q000494:pharmacology; D005455:Fluorescent Antibody Technique; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008558:Melphalan / Q000494:pharmacology*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism
D018941:Antigens, CD19; D018906:Antineoplastic Agents, Alkylating; D051793:Hypoxia-Inducible Factor 1; D034741:RNA, Small Interfering; D004448:Echinomycin; D007334:Insulin-Like Growth Factor I; D019869:Phosphatidylinositol 3-Kinases; D020928:Mitogen-Activated Protein Kinases; D008558:Melphalan