Essential roles of PI-3K/Akt/IKKbeta/NFkappaB pathway in cyclin D1 induction by arsenite in JB6 Cl41 cells

Carcinogenesis. 2006 Apr;27(4):864-73. doi: 10.1093/carcin/bgi321. Epub 2005 Dec 29.


Skin is a major target of carcinogenic trivalent arsenic (arsenite, As3+). It has been thought that cell proliferation is one of the central events involved in the carcinogenic effect of arsenite. Cyclin D1, a nuclear protein playing a pivotal role in cell proliferation and cell cycle transition from G1 to S phases, has been reported to be induced in human fibroblast by arsenite via uncertain molecular mechanisms. In the present study, the potential roles of PI-3K/Akt/IKKbeta/NFkappaB signal pathway in cyclin D1 induction by arsenite were addressed in mouse epidermal Cl41 cells. We found that exposure of Cl41 cells to arsenite was able to induce cell proliferation, activate PI-3K-->Akt/p70(S6k) signal pathway and increase cyclin D1 expression at both transcription and protein levels. Pre-treatment of Cl41 cells with PI-3K inhibitor, wortmannin, significantly inhibited the phosphorylation of Akt and p70(S6k) and thereby dramatically impaired the cyclin D1 induction by arsenite, implicating the importance of the PI-3K signal pathway in the cyclin D1 induction by arsenite. Furthermore, inhibition of PI-3K/Akt by overexpression of Deltap85 or DN-Akt blocked arsenite-induced IKK phosphorylation, IkappaBalpha degradation and cyclin D1 expression, indicating that IKK/NFkappaB is the downstream transducer of arsenite-triggered PI-3K/Akt cascade. Moreover, inhibition of IKKbeta/NFkappaB signal pathway by overexpression of its dominant negative mutant, IKKbeta-KM, also significantly blocked arsenite-induced cyclin D1 expression. Overall, arsenite exposure triggered PI-3K/Akt/IKKbeta/NFkappaB signal cascade which in turn plays essential roles in inducing cyclin D1 expression.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Arsenites / toxicity*
  • Cell Culture Techniques
  • Cell Cycle / drug effects
  • Cell Proliferation / drug effects
  • Cyclin D1 / biosynthesis*
  • Cyclin D1 / drug effects
  • Epidermal Cells
  • I-kappa B Kinase / physiology*
  • Mice
  • NF-kappa B / physiology*
  • Oncogene Protein v-akt / physiology*
  • Phosphatidylinositol 3-Kinases / physiology*
  • Signal Transduction
  • Skin Neoplasms / chemically induced
  • Skin Neoplasms / physiopathology
  • Skin Physiological Phenomena / drug effects
  • Teratogens / toxicity*


  • Arsenites
  • NF-kappa B
  • Teratogens
  • Cyclin D1
  • Phosphatidylinositol 3-Kinases
  • Oncogene Protein v-akt
  • I-kappa B Kinase
  • arsenite