Risk for, and progression of, cancer have been linked to cell proliferation which is not balanced by apoptotic cell death. Although recent studies have focused on the molecular and biochemical events associated with initiation of growth arrest and apoptotic pathways, the mechanisms involved in the coordinate regulation of these pathways remains unclear. There is evidence, however, that mitochondria and mitochondrial activities play a pivotal role. Our previous work has defined depressed mitochondrial function and decreased apoptosis as early components in risk and progression of colon cancer, and established that the metabolism of short-chain fatty acids (SCFAs) such as butyrate induces growth arrest, mitochondrial function and apoptosis in colonic carcinoma cells in vitro. Moreover, we have demonstrated that initiation of SCFA induced growth arrest and apoptotic cascades require mitochondrial function. This application extends our work to the mammary gland, hypothesizing that modulation of mitochondrial function plays a similar role in the coordinate regulation of growth arrest and apoptotic cell death pathways in mammary epithelial cells. Using biochemical and genetic manipulations in culture and a novel genetic model in which mice are rendered incapable of metabolizing SCFAs due to a homozygous deletion in short-chain acyl dehydrogenase (SCAD, the gene catalyzing the first reaction in mitochondrial beta-oxidation of SCFAs) and tributyrin, a stabilized derivative of butyrate, we will define the mechanisms which link SCFAs, their metabolism, mitochondrial function, growth arrest and apoptosis of mammary epithelial cells, and establish that perturbations in such mechanisms affect carcinogen initiated mammary tumorigenesis.
| Heerdt, Barbara G; Houston, Michele A; Wilson, Andrew J et al. (2003) The intrinsic mitochondrial membrane potential (Deltapsim) is associated with steady-state mitochondrial activity and the extent to which colonic epithelial cells undergo butyrate-mediated growth arrest and apoptosis. Cancer Res 63:6311-9 |
| Heerdt, B G; Houston, M A; Mariadason, J M et al. (2000) Dissociation of staurosporine-induced apoptosis from G2-M arrest in SW620 human colonic carcinoma cells: initiation of the apoptotic cascade is associated with elevation of the mitochondrial membrane potential (deltapsim). Cancer Res 60:6704-13 |
