Mechanism of vascular endothelial growth factor expression mediated by cisplatin in human ovarian cancer cells.
Cisplatin (CDDP) and its analogues are widely used for the treatment of a variety of human solid tumors. However, the molecular mechanism of its action remains to be understood. Vascular endothelial growth factor (VEGF) is a potent inducer of angiogenesis and is upregulated in many human cancers. In this study we demonstrated that CDDP-inhibited VEGF expression in human ovarian cancer cells. We found that CDDP inhibited the VEGF reporter activity in a dose-dependent manner, indicating that CDDP-inhibited transcriptional activation of VEGF. We also found that: (1) luciferase activity mediated by the VEGF reporter containing a mutation of the HIF-1 binding site was much lower than that of the reporter containing a wild-type HIF-1 binding site in ovarian cancer cells, thus confirming that HIF-1 is a major transcriptional regulator of VEGF expression; and that (2) CDDP greatly inhibited VEGF reporter activity containing the wild-type but not the mutant HIF-1 binding site. This result indicates that CDDP-inhibited VEGF transcriptional activation specifically by decreasing HIF-1 activity. Co-transfection of a dominant negative construct of HIF-1 inhibited VEGF reporter activity in ovarian cancer cells. CDDP-inhibited VEGF transcriptional activation specifically through the expression of HIF-1alpha, but not HIF-1beta. We demonstrated that VEGF receptor KDR was expressed in ovarian cancer cells, and that CDDP-inhibited VEGF expression was linked with cellular apoptosis, which was rescued by VEGF treatment. These results suggest a novel mechanism of CDDP's anti-tumor activity in ovarian cancer cells via HIF-1 expression and VEGF transcriptional activation.
Zhong
Xiao-Song
XS
Laboratory of Reproductive Medicine, Cancer Center, Nanjing Medical University, Nanjing 210029, Jiangsu, China.
Liu
Ling-Zhi
LZ
Skinner
Heath D
HD
Cao
Zongxian
Z
Ding
Min
M
Jiang
Bing-Hua
BH
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator / Q000378:metabolism; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D010051:Ovarian Neoplasms; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000378:metabolism*
C497396:ARNT protein, human; D000970:Antineoplastic Agents; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D008156:Luciferases; D040301:Vascular Endothelial Growth Factor Receptor-2; D002945:Cisplatin