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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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NEOPLASIA
Bortezomib inhibits tumor adaptation to hypoxia by stimulating the FIH-mediated repression of hypoxia-inducible factor-1
Dong Hoon Shin1,
Yang-Sook Chun2,
Dong Soon Lee3,
L. Eric Huang4, and
Jong-Wan Park1
Departments of1 Pharmacology,
2 Physiology and Cancer Research Institute, and
3 Laboratory Medicine, Seoul National University College of Medicine, Seoul, Korea; and
4 Department of Neurosurgery, University of Utah School of Medicine, Salt Lake City
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-1 (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 subnanomolar 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 coactivator. Specifically, bortezomib targeted HIF-1 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-1 transcriptional activity by reinforcing the FIH-mediated inhibition of p300 recruitment.
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