Mechanism of Vascular Endothelial Growth Factor Expression Mediated by Cisplatin in Human Ovarian Cancer Cells

Details

• Personal Author:
  Cao ZX ; Ding M ; Jiang BH ; Liu LZ ; Skinner HD ; Zhong XS
• Description:
  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-1 alpha, but not HIF-1 beta. 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. [Description provided by NIOSH]
• Subjects:
  Neoplasms Occupational Health Safety Urogenital Diseases Urogenital System Women
• Keywords:
  Cancer Cell-biology Cell-metabolism Cell-morphology Cell-transformation Cellular-reactions Cellular-transport-mechanism Cellular-uptake Humans Reproductive-effects Reproductive-system-disorders Tumor-inhibition Tumors

  More +
• ISSN:
  0006-291X
• Document Type:
  Text
• Genre:
  Journal Article
• Place as Subject:
  OSHA Region 3 ; West Virginia
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Division:
  HELD - Health Effects Laboratory Division
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Pages in Document:
  92-98
• Volume:
  358
• Issue:
  1
• NIOSHTIC Number:
  nn:20032316
• Citation:
  Biochem Biophys Res Commun 2007 Jun; 358(1):92-98
• Email:
  bhjiang@njmu.edu.cn
• CAS Registry Number:
  Cisplatin (CAS RN 15663-27-1)
• Federal Fiscal Year:
  2007
• NORA Priority Area:
  Manufacturing
• Peer Reviewed:
  True
• Source Full Name:
  Biochemical and Biophysical Research Communications
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:4acad578239df961c47eb4adcfcb42e9853051b5b9c11897cf74f8c2111e70154701c4d9e6d69eea1558ff423f8bc9e5ec01e89162bd88d5f0cd049d3e5061c7
• Download URL:
  https://stacks.cdc.gov/view/cdc/186339/cdc_186339_DS1.pdf
• File Type:
  [PDF - 513.44 KB ]