TAILIEUCHUNG - Báo cáo khoa học: Dual effect of echinomycin on hypoxia-inducible factor-1 activity under normoxic and hypoxic conditions

Hypoxia-inducible factor-1 (HIF-1) is now recognized as a possible target for cancer treatment. This transcription factor is responsible for the overex-pression of several genes favouring cancer cell survival and inducing neo-angiogenesis. | ỊFEBS Journal Dual effect of echinomycin on hypoxia-inducible factor-1 activity under normoxic and hypoxic conditions Benoit Vlaminck Sebastien Toffoli Benjamin Ghislain Catherine Demazy Martine Raes and Carine Michiels Laboratory of Biochemistry and Cellular Biology FUNDP-University of Namur Belgium Keywords HIF-1 hypoxia hypoxia-inducible factor-1 inhibitors transcription Correspondence C. Michiels Laboratory of Biochemistry and Cellular Biology FUNDP-University of Namur 61 Rue de Bruxelles 5000 Namur Belgium Fax 32 81 724135 Tel 32 81 724131 E-mail Received 31 May 2007 revised 26 July 2007 accepted 29 August 2007 doi Hypoxia-inducible factor-1 HIF-1 is now recognized as a possible target for cancer treatment. This transcription factor is responsible for the overexpression of several genes favouring cancer cell survival and inducing neoangiogenesis. Echinomycin has recently been described to inhibit HIF-1 DNA binding and transcriptional activity. In this work it is shown that echinomycin strongly inhibits the activity of HIF-1 under hypoxic conditions and also interferes with the activity of other transcription factors. These results demonstrate the lack of specificity of this molecule. Moreover it is demonstrated that echinomycin induces an increase in HIF-1 activity under normoxic conditions parallel to an increase in the expression of HIF-1 target genes. This effect is caused by an increase in HIF-1a protein level resulting from an increase in the transcription of the HIF-1A gene in the presence of a low concentration of echinomycin. Transfection experiments with HIF-1a promoter constructs revealed the presence of an Sp1 binding element responsive to echinomycin. Furthermore echinomycin enhanced Sp1 activity as measured by the use of a specific reporter system. These findings show for the first time that echinomycin has a dual effect on HIF-1 activity under normoxic and hypoxic conditions .

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