Breast cancer cell-targeted oxidative stress: enhancement of cancer cell uptake of conjugated linoleic acid, activation of p53, and inhibition of proliferation.
We investigated the mechanism of inhibition of cell proliferation by mixed isomers of CLA (9-cis, 11-trans CLA; 10-trans, 12-cis CLA) on human, non-tumorigenic MCF10A cells that were derived from mammary ductal epithelial cells and MCF7 cells that were derived from a well differentiation mammary adenocarcinoma. When treated in the log phase of growth, the uptake of CLA by MCF7 exceeded the levels measured in MCF10A cells. Treatment with CLA in the presence of HPO doubled the incorporation of CLA in MCF7 cells, independent of the isomer, but reduced the incorporation of CLA by MCF10A cells. CLA caused tumor cell-targeted increased expression of 4-hydroxy-2-nonenal (4HNE), a product of lipid peroxidation, and decreased proliferation in MCF7 cells, as measured by the incorporation of bromodeoxyuridine (BrdU) and expression of phosphorylated histone H3, and the effects of CLA in combination with HPO on mitosis were greater than the effects of either agent alone. Decreased cell proliferation in CLA-treated MCF7 cells coincided with increased nuclear localization of phosphorylated, activated p53 protein, and decreased nuclear localization of the transcription factor FKHRSer256. Importantly, CLA-treated MCF7 cells were more sensitive than MCF10A cells to HPO-induced 4HNE, expression of p53, and decreased mitotic activity. These studies suggest that tumor cell-targeted increased sensitivity to oxidative stress and activation of p53 play important roles in the regulation of human breast cancer cell proliferation by CLA.
Department of Nutrition, McGavran-Greenberg Building, School of Public Health and School of Medicine, University of North Carolina, Chapel Hill, NC 27599-7461, USA. cdalbrig@email.unc.edu
Craig D
CD
Albright
Erich
E
Klem
Anish A
AA
Shah
Patricia
P
Gallagher
D001943:Breast Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000187:drug effects; D004591:Electrophoresis, Polyacrylamide Gel; D005260:Female; D005455:Fluorescent Antibody Technique; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D006801:Humans; D015151:Immunoblotting; D044243:Linoleic Acids, Conjugated / Q000378:metabolism* / Q000494:pharmacology*; D015227:Lipid Peroxidation / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D014157:Transcription Factors / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000187:drug effects / Q000378:metabolism*
D004268:DNA-Binding Proteins; C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D044243:Linoleic Acids, Conjugated; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53