Up-regulation of cyclin D1 by JNK1/c-Jun is involved in tumorigenesis of human embryo lung fibroblast cells induced by a low concentration of arsenite

Toxicol Lett. 2011 Oct 10;206(2):113-20. doi: 10.1016/j.toxlet.2011.06.024. Epub 2011 Jun 25.

Abstract

Inorganic arsenic, a ubiquitous environmental contaminant, is associated with an increased risk of cancer. There are several hypotheses regarding arsenic-induced carcinogenesis. The mechanism of action remains obscure, although hyper-proliferation of cells is involved. In the present study, the molecular mechanisms underlying the proliferation and malignant transformation of human embryo lung fibroblast (HELF) cells induced by a low concentration of arsenite were investigated. The results reveal that a low concentration of arsenite induces cell proliferation and promotes cell cycle transition from the G(1) to the S phase. Moreover, arsenite activates the JNK1/c-Jun signal pathway, but not JNK2, which up-regulates the expression of cyclin D1/CDK4 and phosphorylates the retinoblastoma (Rb) protein. Blocking of the JNK1/c-Jun signal pathway suppresses the increases of cyclin D1 expression and Rb phosphorylation, which attenuates cell proliferation, reduces the transition from the G1 to the S phase, and thereby inhibits the neoplastic transformation of HELF cells induced by a low concentration of arsenite. Thus, activation of the JNK1/c-Jun pathway up-regulates the expression of cyclin D1, which is involved in the tumorigenesis caused by a low concentration of arsenite.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anticarcinogenic Agents / pharmacology
  • Anticarcinogenic Agents / therapeutic use
  • Arsenites / administration & dosage
  • Arsenites / toxicity*
  • Carcinogens, Environmental / administration & dosage
  • Carcinogens, Environmental / toxicity
  • Cell Line
  • Cell Proliferation / drug effects
  • Cell Transformation, Neoplastic / chemically induced*
  • Cell Transformation, Neoplastic / drug effects
  • Cell Transformation, Neoplastic / metabolism
  • Cell Transformation, Neoplastic / pathology
  • Cyclin D1 / antagonists & inhibitors
  • Cyclin D1 / genetics
  • Cyclin D1 / metabolism*
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism
  • Fibroblasts / pathology
  • Fibroblasts / transplantation
  • G1 Phase / drug effects
  • Humans
  • Lung / drug effects*
  • Lung / metabolism
  • Lung / pathology
  • Lung Neoplasms / chemically induced
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / pathology
  • Lung Neoplasms / prevention & control
  • Mice
  • Mice, Nude
  • Mitogen-Activated Protein Kinase 8 / antagonists & inhibitors
  • Mitogen-Activated Protein Kinase 8 / genetics
  • Mitogen-Activated Protein Kinase 8 / metabolism*
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinase Inhibitors / therapeutic use
  • Proto-Oncogene Proteins c-jun / antagonists & inhibitors
  • Proto-Oncogene Proteins c-jun / genetics
  • Proto-Oncogene Proteins c-jun / metabolism*
  • RNA Interference
  • RNA, Small Interfering
  • Signal Transduction / drug effects
  • Sodium Compounds / administration & dosage
  • Sodium Compounds / toxicity*
  • Up-Regulation / drug effects*

Substances

  • Anticarcinogenic Agents
  • Arsenites
  • CCND1 protein, human
  • Carcinogens, Environmental
  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins c-jun
  • RNA, Small Interfering
  • Sodium Compounds
  • Cyclin D1
  • sodium arsenite
  • Mitogen-Activated Protein Kinase 8