Bortezomib inhibits tumor adaptation to hypoxia by stimulating the FIH-mediated repression of hypoxia-inducible factor-1.
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.
Shin
Dong Hoon
DH
Department of Pharmacology, Seoul National University College of Medicine, Seoul, Korea.
Chun
Yang-Sook
YS
Lee
Dong Soon
DS
Huang
L Eric
LE
Park
Jong-Wan
JW
D000220:Adaptation, Biological / Q000187:drug effects*; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D015687:Cell Hypoxia / Q000187:drug effects; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006899:Mixed Function Oxygenases; D009369:Neoplasms / Q000378:metabolism*; D011719:Pyrazines / Q000494:pharmacology*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects / Q000235:genetics; D050880:p300-CBP Transcription Factors / Q000378:metabolism
D001897:Boronic Acids; C486381:CITED2 protein, human; D004268:DNA-Binding Proteins; D051793:Hypoxia-Inducible Factor 1; D011719:Pyrazines; D012097:Repressor Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D000069286:Bortezomib; D006899:Mixed Function Oxygenases; C439790:HIF1AN protein, human; D050880:p300-CBP Transcription Factors