JNK and ERK signaling pathways in multistage mouse carcinogenesis: studies in the inhibition of signaling cascades as a means to understand their in vivo biological role

Journal URL: http://www.iiar-anticancer.org/main.php?id=2Amplification and mutation of Ha-ras has been shown to correlate with the malignancy of tumors that appear in chemically-induced mouse skin. Cell lines isolated from mouse skin tumors represent the evolutionary stages of tumor development. Due to the high Ha-ras levels the JNK and ERK modules are found elevated, contributing to the enhanced AP-1 activity in the more malignant cells. To examine the role of the transforming Ha-ras in controlling ERK signaling, transaction of an activated Ha-ras allele was tested in a squamous cell carcinoma cell line. The ERK1/2 signaling pathways were blocked pharmacologically by PD98059 MEK inhibitor, which inhibited cell proliferation and anchorage-independent growth of squamous and spindle carcinoma cells. In addition, treatment with PD98059 and introduction of the dominant negative ATE-2 mutant into the spindle carcinoma cells, partially reverted the spindle phenotype to squamous - like. These results suggest that ERK1/2 and ATE-2 play an important role in oncogenicity and in the degree of progression within the mouse skin carcinogenesis system