Involvement of activator protein‐1 (AP‐1) in induction of apoptosis by vitamin E succinate in human breast cancer cells

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Abstract
The purpose of this study was to document induction of apoptosis by vitamin E succinate (VES; RRR‐α‐tocopheryl succinate) in human breast cancer cells in culture and to characterize potential c‐jun involvement. VES at 18.8 μM (10 μg/mL) induced DNA synthesis arrest, reduced total cell numbers, and induced apoptosis in estrogen receptor–positive and estrogen‐responsive MCF‐7 human breast cancer cells. VES at 10 μg/mL induced apoptosis in greater than 60% of cells within 3 d of treatment. Apoptosis was documented by detection of fragmented or condensed nuclei in 4′,6‐diamindino‐2‐phenylindole–stained cells, detection of terminal deoxynucleotidyl transferase–mediated dUTP‐biotin nick‐end labeled DNA, and DNA laddering. Analyses of mRNA and protein levels of candidate molecules involved in apoptosis showed that MCF‐7 cells treated with VES exhibited elevated and persistent expression of c‐jun. MCF‐7 cells stably transfected with a dominant‐negative interfering mutant c‐jun, TAM‐67, and expressing high levels of mutant jun exhibited approximately 50% blockage of VES‐mediated apoptosis. In addition to increased c‐jun expression after VES treatment, VES‐treated MCF‐7 cells exhibited elevated activator protein‐1 (AP‐1) binding activity. Comparisons of AP‐1 binding factors by super‐shift analyses with jun‐specific antibodies in cells sensitive to VES‐induced apoptosis (empty‐vector control 7‐1 cells) and cells resistant to VES‐induced apoptosis (TAM‐67–containing TAM‐9 cells) showed that the sensitive cells expressed c‐jun and jun D and the resistant cells TAM‐67 AP‐1 binding proteins after VES treatment. These studies suggested that c‐jun may be involved in the apoptotic process initiated by VES treatment of human MCF‐7 breast cancer cells. Mol. Carcinog. 19:180–190, 1997.

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