No abstract

We subcloned cell lines from SW620 cells establishing that, despite the dynamic nature of the mitochondrial membrane potential (#y m ), there are significant and stable differences in the intrinsic #y m among cells within an in vitro population of human colonic carcinoma cells. Whereas more dramatic differences in #y m would likely perturb essential mitochondrial functions, the differences in #y m of the subclones did not affect steady-state reactive oxygen species levels, electron transport activity, or cellular viability and growth rates. However, the differences in intrinsic #y m had a significant effect on the tumorigenic behavior of the cells. Subcloned cell lines with higher #y m were more likely to exhibit elevated steady-state levels of vascular endothelial growth factor and matrix metalloproteinase 7, and increased invasive behavior (properties associated with tumor progression), than cells with lower intrinsic #y m , whereas cells with lower #y m were more likely to respond to the chemopreventive activities of butyrate, including #y m dissipation, growth arrest, and apoptosis, than cells with higher #y m . Therefore, these data establish that the probability for tumor development and progression is linked to stable differences in the intrinsic #y m of colonic epithelial cells.

Development of malignant transformation in the colonic mucosa includes disruption in the equilibrium between proliferation and apoptosis, decreased expression and deletions of the mitochondrial genome, alterations in mitochondrial enzymatic activity, and elevations in the mitochondrial membrane potential (#Ym). Focusing on the role of the #Ym in tumor development and progression, we generated novel isogenic colonic carcinoma cell lines that exhibit highly significant, stable differences in their intrinsic #Ym. Using these cell lines, we have recently shown that the intrinsic #Ym has a significant influence on steady state mitochondrial activity and the extent to which cells enter butyrate-mediated growth arrest and apoptotic cascades. Here, we report that the #Ym is also profoundly linked to important tumorigenic properties of the cells. Compared with cells with lower #Ym, cells with elevated intrinsic #Ym have an enhanced capacity to (a) respond to hypoxia by avoiding apoptosis and initiating angiogenesis, (b) escape anoikis and grow under anchorage-independent conditions, and (c) invade the basement membrane. Combined with our previous work, these data implicate the intrinsic #Ym of colonic carcinoma cells in determining the probability of tumor expansion and progression. (Cancer Res 2006; 66(3): 1591-6)