Chemical carcinogen, N-methyl-N'-nitro-N-nitrosoguanidine, is a specific activator of oncogenic Ras

N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) is a well-known chemical carcinogen that is widely used for animal carcinogenesis model. Treatment of MNNG, through drinking-water, can evoke multiple tumors in gastro-intestinal tract. In addition, MNNG shows the synergic effect with infection such as H. pylori on gastric cancer formation. Although tumorigenic ability of MNNG is known to be related with DNA alkylation, however, recent reports suggested that MNNG-induced tumors do not show the difference in DNA methylation, and genetic mutation profile is quite different from similar DNA alkylating agent, MNU-inducing cancer. Otherwise, genetic mutation of Ras is frequently detected in MNNG-induced tumors. Considering them, tumorigenic property of MNNG would be related with Ras. So we checked the effect of MNNG on Ras pathway. In this study, we demonstrated that MNNG could activate Ras-MAPK pathway as oncogenic Ras dependent manner. Activation of Erk by MNNG could not suppressed by cycloheximide and ALLN. In addition, Inhibition of PI3K, p38/HOG1, Raf, and CDK could not block the MNNG-induced p-Erk activation, whereas U0126 and PD98059 abolished it. Moreover, MNNG could reduce the expression of E-cadherin and promote dissociation of beta-catenin from E-cadherin through oncogenic-Ras-MAPK pathway. These results strongly suggested that oncogenic Ras would be direct target of MNNG and provided new insight that carcinogen also possesses it specific target.