Diethyldithiocarbamate suppresses an NF-kappaB dependent metastatic pathway in cholangiocarcinoma cells

Asian Pac J Cancer Prev. 2013;14(7):4441-6. doi: 10.7314/apjcp.2013.14.7.4441.

Abstract

Cholangiocarcinoma (CCA) is a tumor of biliary ducts, which has a high mortality rate and dismal prognosis. Constitutively activation of the transcription factor nuclear factor kappa-B (NF-κB) has been previously demonstrated in CCA. It is therefore a potential target for CCA treatment. Effects of diethyldithiocarbamate (DDTC) on NF-κB-dependent apoptosis induction in cancer have been reported; however, anti-metastasis has never been addressed. Therefore, here the focus was on DDTC effects on CCA migration and adhesion. Anti-proliferation, anti-migration and anti-adhesion activities were determined in CCA cell lines, along with p65 protein levels and function. NF-κB target gene expression was determined by quantitative RT-PCR. DDTC inhibited CCA cell proliferation. Suppression of migration and adhesion were observed prior to anti-CCA proliferation. These effects were related to decreased p65, reduction in NF-κB DNA binding, and impaired activity. Moreover, suppression of ICAM-1 expression supported NF-kB-dependent anti-metastatic effects of DDTC. Taken together, DDTC suppression of CCA migration and adhesion through inhibition of NF-κB signaling pathway is suggested from the current study. This might be a promising treatment choice against CCA metastasis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects
  • Bile Duct Neoplasms / drug therapy
  • Bile Duct Neoplasms / metabolism
  • Bile Duct Neoplasms / pathology*
  • Bile Ducts, Intrahepatic / drug effects*
  • Bile Ducts, Intrahepatic / metabolism
  • Blotting, Western
  • Cell Adhesion / drug effects
  • Cell Movement / drug effects
  • Cell Proliferation / drug effects
  • Chelating Agents / pharmacology*
  • Cholangiocarcinoma / drug therapy
  • Cholangiocarcinoma / metabolism
  • Cholangiocarcinoma / pathology*
  • Ditiocarb / pharmacology*
  • Electrophoretic Mobility Shift Assay
  • Humans
  • Intercellular Adhesion Molecule-1 / genetics
  • Intercellular Adhesion Molecule-1 / metabolism*
  • NF-kappa B / genetics
  • NF-kappa B / metabolism*
  • RNA, Messenger / genetics
  • Real-Time Polymerase Chain Reaction
  • Reverse Transcriptase Polymerase Chain Reaction
  • Tumor Cells, Cultured
  • Wound Healing

Substances

  • Chelating Agents
  • NF-kappa B
  • RNA, Messenger
  • Intercellular Adhesion Molecule-1
  • Ditiocarb