2,2′,4,6,6′-pentachlorobiphenyl (PCB 104) induces apoptosis of human microvascular endothelial cells through the caspase-dependent activation of CREB

Yong Woo Lee, Hyen Joo Park, Kwang Won Son, Bernhard Hennig, Larry W. Robertson, Michal Toborek

Research output: Contribution to journalArticlepeer-review

34 Scopus citations


It has been proposed that endothelial integrity can play an active regulatory role in the extravasation of tumor cells during cancer metastasis. Since polychlorinated biphenyls (PCBs) have been shown to cause endothelial cell activation or injury and to lead to various diseases that involve dysfunction of the vascular endothelium, the present study was designed to determine the cellular and molecular signaling mechanisms of PCB-induced apoptosis in human microvascular endothelial cells (HMEC-1). A significant and marked decrease in cell viability was observed in HMEC-1 treated with 2,2′,4,6,6′-pentachlorobiphenyl (PCB 104) in a time- and dose-dependent manner. Exposure of HMEC-1 to PCB 104 also dramatically induced internucleosomal DNA fragmentation. However, the caspase inhibitor zVAD-fmk significantly reversed the PCB 104-induced DNA fragmentation in HMEC-1, suggesting that endothelial cell death induced by PCB 104 exposure is, at least in part, due to caspase-dependent apoptotic pathways. To elucidate the molecular signaling mechanisms of PCB 104-induced apoptotic cell death in human microvascular endothelial cells, the present study focused on the effects of acute exposure of PCB 104 on the activation of several transcription factors, such as cAMP responsive element-binding protein (CREB), activator protein-1 (AP-1), nuclear factor-κB (NF-κB), and signal transducers and activators of transcription (STAT1), which have been known to play a pivotal role in the molecular signaling cascades for the induction of apoptosis. A series of electrophoretic mobility shift assay showed that PCB 104 specifically increased only CREB DNA-binding activity in a dose-dependent manner. AP-1, NF-κB, and STAT1, however, were not activated. In addition, zVAD-fmk significantly and dose-dependently blocked the CREB activation enhanced by PCB 104 exposure. These results suggest that PCB-induced death of human microvascular endothelial cells is mediated, at least in part, via the caspase-dependent apoptotic pathways and that the selective activation of CREB is involved in this process.

Original languageEnglish
Pages (from-to)1-10
Number of pages10
JournalToxicology and Applied Pharmacology
Issue number1
StatePublished - May 15 2003

Bibliographical note

Funding Information:
This project was supported by grants from the National Institute of Environmental Health Science, NIH (Grant P42 ES 07380), and the Department of Defense (Grant DAMD17-99-1-9247). It contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIEHS, NIH, and DOD.


  • Apoptosis
  • CREB
  • Caspases
  • Endothelial cells
  • Metastasis
  • PCBs

ASJC Scopus subject areas

  • Toxicology
  • Pharmacology


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