A lipid-soluble iron chelator alters cell cycle regulatory protein binding in breast cancer cells compared to normal breast cells.
The lipid-soluble iron chelator desferri-exochelin (D-Exo) causes reversible cell cycle arrest in normal human mammary epithelial cells (NHMEC) but triggers apoptotic cell death in human breast cancer cells. We studied the effects of iron chelation with D-Exo on cell cycle regulatory proteins in cultures of NHMEC and MCF-7 breast cancer cells. In co-immunoprecipitation studies, D-Exo inhibited binding of cyclins A and E to cyclin dependent kinase 2 (CDK2) in NHMEC, but in MCF-7 cells binding of these cyclins to CDK2 was enhanced. D-Exo treatment markedly increased expression of p53 and increased binding of p21 to CDK2 in the MCF-7 cells but not in NHMEC. Therefore differences in effects of iron chelation on cell cycle protein binding in cancer cells compared to normal cells may trigger apoptosis in cancer cells while normal breast cells are spared.
Pahl
Paula M B
PM
University of Colorado Health Sciences Center, 4200 E. 9th Ave., Denver, CO 80262, USA.
Reese
Sara M
SM
Horwitz
Lawrence D
LD
D017209:Apoptosis / Q000187:drug effects; D001940:Breast / Q000166:cytology / Q000378:metabolism*; D001943:Breast Neoplasms / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000187:drug effects* / Q000378:metabolism; D045744:Cell Line, Tumor; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D016213:Cyclins / Q000378:metabolism; D005260:Female; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000096:biosynthesis; D007502:Iron Chelating Agents / Q000737:chemistry / Q000494:pharmacology*; D010456:Peptides, Cyclic / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects; D012995:Solubility; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D051793:Hypoxia-Inducible Factor 1; D007502:Iron Chelating Agents; D010456:Peptides, Cyclic; D016159:Tumor Suppressor Protein p53; C410730:desferriexochelin 772SM; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases