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Blood, 15 March 2008, Vol. 111, No. 6, pp. 3131-3136.
Prepublished online as a Blood First Edition Paper on January 3, 2008; DOI 10.1182/blood-2007-11-120576.
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Submitted November 20, 2007
Accepted December 20, 2007
Bortezomib inhibits tumor adaptation to hypoxia by stimulating the FIH-mediated repression of hypoxia-inducible factor-1
Dong Hoon Shin, Yang-Sook Chun, Dong Soon Lee, L. Eric Huang, and Jong-Wan Park*
Department of Pharmacology, Seoul National University College of Medicine, Seoul, Korea, Republic of
Department of Physiology and Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea, Republic of
Department of Laboratory Medicine, Seoul National University College of Medicine, Seoul, Korea, Republic of
Department of Neurosurgery, University of Utah School of Medicine, Salt Lake City, UT, United States
Deartment of Pharmacology, Seoul National University College of Medicine, Seoul, Korea, Republic of
* Corresponding author; email: parkjw{at}snu.ac.kr.
Bortezomib (Velcade or 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 HIF-1 . 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 sub-nanomolar concentrations in multiple myeloma and liver cancer cell-lines, regardless of cytotoxic concentrations of bortezomib. Bortezomib repressed HIF-1 activity by inhibiting the recruitment of p300 co-activator. Specifically, bortezomib targeted HIF-1 C-terminal transactivation domain (CAD) but not the CAD lacking Asn803, which is a hydroxylation site by 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-1 transcriptional activity by reinforcing the FIH-mediated inhibition of p300 recruitment.
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