Dibenzo[a,l]pyrene (DB[a,l]P) is the most potent carcinogen among the studied polycyclic aromatic hydrocarbons (PAH) found in smoke from organic matter. Its high ability to induce tumors in the SENCAR mouse skin cancer model appears to be a function of two successive events: mutagenesis to form oncogenic H-ras (codon 61 CAA to CTA) mutations (6-24 h after treatment), followed by unpromoted proliferation of skin cells (24-48 h) carrying these mutations (J Invest Dermatol 125: 567-574, 2005). These conclusions were reached from the observation of selective incremental increases in codon 61 mutations in the H-ras mutation spectra, increases in the levels of replication markers such as PCNA and Ku70 in this period. During the proliferation of codon 61-mutated cells in the skin, an elevation in GTP-bound H-ras protein was observed, suggesting that signaling by activated H-ras could be a mechanism for the proliferation. On the other hand, mouse skin treated with anti-DB[a,l]P-diolepoxide alone, or supplemented (10%) with DB[a,l]P, did not show a clonal increase in H-ras codon 61 mutations. Western blot analysis of skin extracts showed induction in the levels of cyclin E during the proliferation of codon 61-mutant cells in DB[a,l]P-treated skin. This was also seen in anti-DB[a,l]P-diolepoxide-treated skin, where this cell proliferation is not found. In both cases, there was no detectable increase in cyclins D1 and D2 or the ERK1/2 proteins during this period. On the other hand, DB[a,l]P-treated skin showed an increase in the levels of PI3K, AKT, p-AKT and p27, which was not observed in anti-DB[a,l]P-diolepoxide-treated skin. These results raise the possibility that the early unpromoted proliferation of H-ras codon 61-mutated cells may be mediated by activated H-ras signaling through the PI3K/AKT pathway (Supported by NIH grants P20-RR017675 and PO1 CA 49210).
[Proc Amer Assoc Cancer Res, Volume 47, 2006]