S-Space College of Medicine/School of Medicine (의과대학/대학원) Dept. of Physiology (생리학교실) Journal Papers (저널논문_생리학교실)
Bortezomib inhibits tumor adaptation to hypoxia by stimulating the FIH-mediated repression of hypoxia-inducible factor-1
- Shin, Dong Hoon; Chun, Yang-Sook; Lee, Dong Soon; Huang, L Eric; Park, Jong-Wan
- Issue Date
- American Society of Hematology
- Blood. 2008;111(6):3131-3136
- Adaptation, Biological/*drug effects; Boronic Acids/*pharmacology; Cell Hypoxia/drug effects; Cell Line; DNA-Binding Proteins/metabolism; Humans; Hypoxia-Inducible Factor 1/antagonists & inhibitors/genetics/*metabolism; Neoplasms/*metabolism; Pyrazines/*pharmacology; Repressor Proteins/genetics/*metabolism; Trans-Activators/metabolism; Transcription Factors/genetics/*metabolism; Transcription, Genetic/drug effects/genetics; p300-CBP Transcription Factors/metabolism
- Bortezomib (PS-341), a proteasome inhibitor, has been examined clinically for the treatment of multiple myeloma and several solid tumors. Bortezomib directly induces tumor cell death and has also been reported to inhibit tumor adaptation to hypoxia by functionally inhibiting hypoxia-inducible factor-1alpha (HIF-1alpha). However, the mechanism underlying HIF-1 inhibition by bortezomib remains obscure. In the present study, we demonstrated that bortezomib attenuated the hypoxic induction of erythropoietin and vascular endothelial growth factor at subnanomolar concentrations in multiple myeloma and liver cancer cell lines, regardless of cytotoxic concentrations of bortezomib. Bortezomib repressed HIF-1alpha activity by inhibiting the recruitment of p300 coactivator. Specifically, bortezomib targeted HIF-1alpha C-terminal transactivation domain (CAD) but not the CAD lacking Asn803, which is a hydroxylation site by the factor inhibiting HIF-1 (FIH). Accordingly, this effect of bortezomib on CAD was augmented by FIH expression and abolished by FIH knock-down. Furthermore, bortezomib stimulated the interaction between CAD and FIH under hypoxic conditions, and FIH inhibition reversed the suppressions of erythropoietin and vascular endothelial growth factor by bortezomib. We propose that the mechanism underlying the inhibitory effects of bortezomib on tumor angiogenesis and hypoxic adaptation involves the repression of HIF-1alpha transcriptional activity by reinforcing the FIH-mediated inhibition of p300 recruitment.
- 0006-4971 (Print)
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