Mouse skin tumorigenicity studies indicate that benzo[a]-pyrene-7,8-diol-9, 10-epoxide (B[a]PDE) contributes to carcinogenesis as both a tumor initiator and promoter. However, the mechanisms that mediate B[a]PDE tumor promotion effects remain unclear. Our results demonstrated that in mouse epidermal C141 cells, B[a]PDE treatment resulted in marked activation of AP-1 and its upstream MAPKs, including ERKs, JNKs and p38K. B[a]PDE exposure also led to activation of phosphotidylinositol 3-kinase (PI-3K), Akt and p70 S6 kinase (p70 S6k). B[a]PDE-induced AP-1 transactivation was inhibited by pretreatment of cells with PI-3K inhibitors, wortmannin or Ly294002. In contrast, inhibition of p70S6k with rapamycin did not show any inhibitory effects. An overexpression of dominant-negative mutant of PI-3K, Δp85, impaired B[a]PDE-induced activation of PI-3K, Akt and AP-1 transactivation. Furthermore, an overexpression of dominant-negative Akt mutant, Akt-T308A/S473A, blocked B[a]PBE-induced activation of Akt, AP-1 and JNKs, while it did not affect the activation of p70S6k, ERKs and p38 kinase. These results demonstrated that B[a]PBE was able to induce AP-1 transactivation and this AP-1 induction was specific through PI-3K/Akt/JNKs-dependent and p70S6k-independent pathways. This study also indicated that Akt-T308A/ S473A blocks B[a]PDE-induced AP-1 activation specific through impairing JNK pathway. These findings will help us to understand the signal transduction pathways involved in the carcinogenic effects of B[a]PDE.
|Number of pages||13|
|State||Published - May 13 2004|
Bibliographical noteFunding Information:
We thank Jane Galvin for secretarial support. This work was supported in part by grants from National Institutes of Health (NIH)/National Cancer Institute (CA094964, CA103180, and CA112557) and NIH/National Institute of Environmental Health Sciences (ES012451).
- MAP kinase
ASJC Scopus subject areas
- Molecular Biology
- Cancer Research