Jan 9, 2009

Inhibition of HIF-1alpha activity by homeodomain-interacting protein kinase-2 correlates with sensitization of chemoresistant cells to undergo apoptosis

Molecular Cancer
Lavinia NardinocchiGabriella D'Orazi

Abstract

Homeodomain-interacting protein kinase-2 (HIPK2), a transcriptional co-repressor with apoptotic function, can affect hypoxia-inducible factor 1 (HIF-1) transcriptional activity, through downmodulation of its HIF-1alpha subunit, in normoxic condition. Under hypoxia, a condition often found in solid tumors, HIF-1alpha is activated to induce target genes involved in chemoresistance, inhibition of apoptosis and tumor progression. Here, we investigated whether the HIPK2 overexpression could downregulate HIF-1alpha expression and activity in tumor cells treated with hypoxia-mimicking condition, and evaluated whether HIPK2-dependent downregulation of HIF-1alpha could sensitize chemoresistant tumor cells to adriamycin (ADR)-induced apoptosis. Tumor cell lines carrying wild-type p53, siRNA p53, or mutant p53 were overexpressed with HIPK2 (full length or catalytic inactive mutant) and treated with cobalt chloride (CoCl2) to mimic hypoxia, in the presence or absence of ADR treatment. HIF-1alpha expression was measured by semiquantitative reverse-transcriptase (RT)-PCR and Western immunoblotting and HIF-1 activity was evaluated by luciferase assay using reporter plasmid containing hypoxia response elements (HREs) upstream of luciferase gen...Continue Reading

Mentioned in this Paper

Tumor Cells, Uncertain Whether Benign or Malignant
Biochemical Pathway
Gene Expression Regulation, Neoplastic
Transfection
Heat-Shock Proteins 70
Antibiotic Resistance, Neoplasm
Transcription Repressor/Corepressor
Apoptosis, Intrinsic Pathway
Epoetin Alfa
HIF1A wt Allele

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