Abstract
We have established previously that minor subpopulations of cells with stable differences in their intrinsic mitochondrial membrane potential (Δψm) exist within populations of mammary and colonic carcinoma cells and that these differences in Δψm 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 Δψm 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 Δψm, we investigated whether endogenous differences in MUC1 levels were linked to stable differences in intrinsic Δψm and/or to the tumor phenotypes associated with the intrinsic Δψm. We report that levels of MUC1 are significantly higher in subpopulations of cells with elevated intrinsic Δψm 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 Δψm or the tumor phenotypes associated with increased intrinsic Δψm. Moreover, whereas pharmacologically mediated disruption of the Δψm 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 Δψm, it is not directly linked to the generation or maintenance of stable alterations in intrinsic Δψm, or to intrinsic Δψm associated tumor phenotypes. Since the Δψm 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 Δψm and are most likely to contribute to tumor progression.
Highlights
Heterogeneity is a fundamental property of cellular systems, including solid tumors [1], where diversity likely provides reservoirs of cells which, through evasion of preventative or therapeutic intervention and/or tolerance and rapid response to shifting micro-environmental conditions, can participate in tumor expansion and progression
mucin 1 (MUC1) mRNA levels are at least 1.5 fold, and as much as 6 fold, higher in the subcloned cell lines with elevated Dym (*P,0.001 vs. the population of SW620 cells). To investigate whether this relationship between MUC1 mRNA and intrinsic Dym extended to MUC1 C-ter protein levels, mitochondrial and accompanying Post Mitochondrial (PMF) enriched fractions were isolated from the SW620 colonic carcinoma cell population and from subcloned lines derived from SW620 cells with a range of relative intrinsic Dym [1]
Because MUC1 is over-expressed in many human carcinomas and cell lines where it is associated with tumor progression [9,22], we investigated the relationship between intrinsic Dym and endogenous MUC1 expression
Summary
Heterogeneity is a fundamental property of cellular systems, including solid tumors [1], where diversity likely provides reservoirs of cells which, through evasion of preventative or therapeutic intervention and/or tolerance and rapid response to shifting micro-environmental conditions, can participate in tumor expansion and progression. Our previous work has established that within populations of colonic and mammary carcinoma cells there are minor subpopulations of cells that exhibit stable differences in intrinsic mitochondrial membrane potential (Dym) which are linked to tumorigenic phenotypes [1,2]. MUC1 is synthesized as a single polypeptide which is cleaved into an N-terminal extra cellular fragment (MUC1 N-ter) and a C-terminal fragment (MUC1 Cter), which includes transmembrane and cytoplasmic domains. The cytoplasmic domain of MUC1 C-ter (MUC1-CD) interacts with diverse signal transducing molecules [9,11,12,13,14], and has been linked to transcriptional regulation of various genes [15,16] including VEGF [15,16,17]. Mitochondrial (mt)-associated MUC1 Cter has been reported to attenuate dissipation of the Dym and subsequent apoptosis initiated through the intrinsic (mitochondrial mediated) pathway [13,14,15,18,19,20,21]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
