Participation of a MEK-independent pathway in MAP kinase activation and modulation of cell growth in mouse hepatoma cell lines

The mechanism of cell growth was investigated in GIT medium-supplemented in vitro assay using high and low metastatic mouse hepatoma cell sublines, G- 5 and G-1, respectively. G-5 cells exhibited high growth rate compared to G -1 cells. The PI3-kinase inhibitor LY294002 and P70 S6 kinase inhibitor rap amycin partially blocked both G-1 and G-5 cell growth, suggesting that thes e two kinases are involved in hepatoma cell growth. In contrast, the MEK1 i nhibitor PD98059 partially blocked G-5 cell growth but not G-1 cell growth. MAP kinases (MAPK) in both G-1 and G-5 cells were indistinguishably phosph orylated, yet MEK-dependent MAPK activation was observed only in G-5 cells. In G-1 cells, MAPK was phosphorylated in a manner not connected to MEK act ivation. Thus, the low degree of cell growth in G-1 cells was attributable to disruption of the MEK-dependent MAPK cascade. However, the molecular mec hanism whereby MAPK phosphorylation does not parallel MAPK activation in G- 1 cells remains unknown. Here, we suggest that there may be an as yet unide ntified MAPK phosphorylation pathway in malignantly transformed cells, whic h may affect in vitro cell growth and metastatic capacities of cancers.