title: Cisplatin and doxorubicin repress Vascular Endothelial Growth Factor expression and differentially down-regulate Hypoxia-inducible Factor I activity in human ovarian cancer cells.
abstract: Vascular Endothelial Growth Factor (VEGF) and its transcriptional regulator Hypoxia-inducible Factor 1 (HIF-1) play an important role in the process of angiogenesis in many types of cancer, including ovarian cancer. We have examined whether the DNA-damaging drugs cisplatin and doxorubicin and the microtubule inhibitors docetaxel and paclitaxel can affect VEGF expression and HIF-1 activity in three human ovarian cancer cell lines. We demonstrate that cisplatin and doxorubicin abolish hypoxia-induced VEGF mRNA expression in all cell lines, while basal VEGF mRNA expression was also downregulated. Transient transfection with a HIF-1-responsive luciferase construct indicated that cisplatin and doxorubicin inhibited hypoxic activation of HIF-1. Cisplatin repressed HIF-1alpha protein expression in all cell lines. Stimulation of HIF-1alpha protein degradation by cisplatin was observed in the only cell line expressing wild-type p53. Cisplatin also inhibited the synthesis of HIF-1alpha protein for which p53 was dispensable. Interestingly, cisplatin strongly reduced the protein levels of the HIF-1 coactivators p300 and CREB-binding protein (CBP) under hypoxia in all cell lines. Although doxorubicin inhibited hypoxic activation of HIF-1, this drug had no significant effect on the expression levels of HIF-1alpha and hypoxic expression of p300 and CBP was only weakly reduced. Docetaxel and paclitaxel did neither influence VEGF expression nor hypoxia-induced HIF-1 activity. In total, our findings indicate that cisplatin and doxorubicin can repress hypoxic induction of VEGF expression by inhibiting HIF-1 through different mechanisms. This knowledge may be useful for future treatment schedules including agents that target the HIF-1 signalling pathway.
authors.affiliation: Department of Medical Oncology, VU University medical center, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands.
authors.forename: Monique C A
authors.initials: MC
authors.lastname: Duyndam
authors.forename: Maria P A
authors.initials: MP
authors.lastname: van Berkel
authors.forename: Josephine C
authors.initials: JC
authors.lastname: Dorsman
authors.forename: Davy A P
authors.initials: DA
authors.lastname: Rockx
authors.forename: Herbert M
authors.initials: HM
authors.lastname: Pinedo
authors.forename: Epie
authors.initials: E
authors.lastname: Boven
mesh_terms: D000951:Antigens, Neoplasm / Q000235:genetics; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D003345:Corticosterone; D015536:Down-Regulation; D004317:Doxorubicin / Q000494:pharmacology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics*; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics*; D050880:p300-CBP Transcription Factors / Q000235:genetics
chemical_list: D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D002352:Carrier Proteins; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D042461:Vascular Endothelial Growth Factor A; D004317:Doxorubicin; D050880:p300-CBP Transcription Factors; C089226:CA9 protein, human; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases; D002945:Cisplatin; D003345:Corticosterone