Phosphatidylinositol-3 kinase/Akt/p70S6K/AP-1 signaling pathway mediated benzo(a)pyrene-induced cell cycle alternation via cell cycle regulatory proteins in human embryo lung fibroblasts

Ai Gao, Bingci Liu, Xianglin Shi, Xiaowei Jia, Meng Ye, Shi Jiao, Baorong You, Chuanshu Huang

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

Abstract

Benzo(a)pyrene (B(a)P), a potent environmental procarcinogen, has been shown to cause cell cycle alternation. However, the mechanisms involved in this effect are not well understood yet. Our current results demonstrated that B(a)P exposure led to cell proliferation and a 33.5% increase in S phase cells as well as a 26.8% decrease in G1 phase cells in human embryo lung fibroblasts (HELFs). Those cell cycle alternations were accompanied with transactivation of activator protein-1 (AP-1) and phosphorylation of Akt and p70S6K. These changes were blocked by overexpression of dominant negative mutants of phosphatidylinositol-3 kinase (Δp85) or Akt (DN-Akt), respectively. Moreover, pretreatment of cells with rapamycin, a specific p70S6K inhibitor, inhibited B(a)P-induced AP-1 activation, cell cycle alteration and phosphorylation of p70S6K, but had no effect on Akt phosphorylation. Our results, therefore, suggest that phosphatidylinositol-3 kinase (PI-3K)/Akt/p70S6K/AP-1 pathway participates in B(a)P-induced cell cycle alternations. Furthermore, we explored the effect of this pathway on cell cycle regulatory proteins. B(a)P markedly increases in the expression of cyclin D1 and E2F1 and phosphorylation of retinoblastoma protein (Rb). In addition, we found that inactivation of PI-3K, Akt or p70S6K could eliminate those effects on cell cycle regulatory proteins. Collectively, PI-3K/Akt/p70S6K/AP-1 pathway mediated B(a)P-induced alternation of cell cycle through regulation of cell cycle regulatory proteins such as cyclin D1, E2F1, and Rb in HELFs.

Original languageEnglish
Pages (from-to)30-41
Number of pages12
JournalToxicology Letters
Volume170
Issue number1
DOIs
StatePublished - Apr 5 2007

Bibliographical note

Funding Information:
This work was supported in part by grants of National Natural Science Foundation of China (30371206, 30440420593) (B.L.), 973 National Key Basic Research and Development Program (2002 CB 512905)(B.L.), One Hundred Talents program of Chinese Academy of Sciences, and also supported in part by Philip Morris USA Inc and Philip Morris International (X.S.) and by NIH/NIEHS (ES012451) (C.H.).

Keywords

  • Akt
  • B(a)P
  • Cell cycle
  • Signaling pathway
  • p70

ASJC Scopus subject areas

  • Toxicology

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