Intrinsic Mitochondrial Membrane Potential and Associated Tumor Phenotype Are Independent of MUC1 Over-Expression

We have established previously that minor subpopulations of cells with stable differences in their intrinsic mitochondrial membrane potential (Delta psi m) exist within populations of mammary and colonic carcinoma cells and that these differences in Delta psi m are linked to tumorigenic phenotypes consistent with increased probability of participating in tumor progression. However, the mechanism(s) involved in generating and maintaining stable differences in intrinsic Delta psi m and how they are linked to phenotype are unclear. Because the mucin 1 (MUC1) oncoprotein is over-expressed in many cancers, with the cytoplasmic C-terminal fragment (MUC1 C-ter) and its integration into the outer mitochondrial membrane linked to tumorigenic phenotypes similar to those of cells with elevated intrinsic Delta psi m, we investigated whether endogenous differences in MUC1 levels were linked to stable differences in intrinsic Delta psi m and/or to the tumor phenotypes associated with the intrinsic Delta psi m. We report that levels of MUC1 are significantly higher in subpopulations of cells with elevated intrinsic Delta psi m derived from both mammary and colonic carcinoma cell lines. However, using siRNA we found that down-regulation of MUC1 failed to significantly affect either the intrinsic Delta psi m or the tumor phenotypes associated with increased intrinsic Delta psi m. Moreover, whereas pharmacologically mediated disruption of the Delta psi m was accompanied by attenuation of tumor phenotype, it had no impact on MUC1 levels. Therefore, while MUC1 over-expression is associated with subpopulations of cells with elevated intrinsic Delta psi m, it is not directly linked to the generation or maintenance of stable alterations in intrinsic Delta psi m, or to intrinsic Delta psi m associated tumor phenotypes. Since the Delta psi m is the focus of chemotherapeutic strategies, these data have important clinical implications in regard to effectively targeting those cells within a tumor cell population that exhibit stable elevations in intrinsic Delta psi m and are most likely to contribute to tumor progression.