Resistance to apoptosis induced by microenvironmental stresses is correlated with metastatic potential in Lewis lung carcinoma

The apoptosis-resistant phenotype of cloned high-metastatic A11 and low-met astatic P29 cells isolated from Lewis lung carcinoma was compared. The resu lts showed that A11 cells were more resistant to apoptosis induced by micro environmental stresses such as serum starvation, glucose deprivation and hy poxia than P29 cells as judged by viability, DNA laddering, and chromatin c ondensation and fragmentation. Both cell lines were insensitive to tumor ne crosis factor-alpha-mediated apoptosis. P29 cells expressed a much higher l evel of Fas antigen on the cell surface than A11 cells. However, both cell lines were also insensitive to Fas-mediated apoptosis. The apoptosis resist ant phenotype of A11 cells was associated with the expression level of casp ase-3, but not with those of Bcl-2, Bcl-X-L Bax, p27(Kip1) and DAP kinase. There was no difference between A11 and P29 cells in the expression of E-ca dherin, the adhesiveness to the extracellular matrix components or the expr ession levels of metastasis-associated genes such as c-Ha-ras, c-jun, p53 a nd nm23. Furthermore, A11 cells exhibited lower motile and invasive abiliti es than P29 cells. These results suggest that the apoptosis-resistant pheno type is an important factor for determining the metastatic ability of A11 c ells. Supporting this, P29 cells became more apoptosis-resistant after trea tment of the cells with dimethylsulfoxide which is reported to enhance the experimental metastatic potential of the cells.