Distinct patterns of mitochondrial changes precede induction of apoptosis by all-trans-retinoic acid and N-(4-hydroxyphenyl)retinamide in MCF7 breast cancer cells |
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Authors: | Poot Martin Hosier Suzanne Swisshelm Karen |
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Affiliation: | Department of Pathology, University of Washington, Seatle, Washington 98195-7705, USA. MartinP@medicine.washington.edu |
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Abstract: | The biochemical mechanisms of apoptosis-induction by all-trans-retinoic acid (atRA) and N-(4-hydroxyphenyl)retinamide (4HPR) in cultured MCF7 cancer cells were studied by multiparameter flow cytometry. Retinoid treatment induced formation of two biochemically distinct cell subpopulations, which preceded the appearance of cells with fragmented nuclei. Exposure to atRA led to a transient increase in NADH level and mitochondrial oxidative turnover and a slow decline in reduced thiol level and mitochondrial membrane potential, suggesting that atRA treatment induces a transient defense mechanism. The synthetic retinoid 4HPR, in contrast, caused a gradual decrease in mitochondrial oxidative turnover and cardiolipin level together with a small decline in mitochondrial membrane potential, suggesting that 4HPR induces oxidation of cardiolipin and subsequent leakage of the mitochondria. Co-incubation with cyclosporin A, an inhibitor of the mitochondrial permeability transition, did not prevent formation of fragmented nuclei or induction of changes in mitochondrial parameters by retinoids. Thus, the mitochondrial permeability transition does not appear to be involved in retinoid induction of apoptosis in MCF7 cells. Retinoid exposure of diploid human mammary epithelial cells induced mild oxidative stress but did not lead to formation of two cell subpopulations. We conclude that atRA and 4HPR induce apoptosis in MCF7 cells by two distinct and novel biochemical mechanisms. |
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Keywords: | all-trans-retinoic acid (atRA) N-(4-hydroxyphenyl)retinamide (4HPR) MCF7 breast cancer cells flow cytometry apoptosis mitochondrial membrane potential NADH level mitochondrial oxidative turnover cardiolipin |
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