Vitamin E inhibition of normal mammary epithelial cell growth is associated with a reduction in protein kinase Cα activation

Authors


Dr Paul W. Sylvester, College of Pharmacy, University of Louisiana at Monroe, Monroe, LA 71209–0470, USA. Tel.: 318 342 1958, Fax: 318 342 1606, E-mail: pysylvester@ulm.edu

Abstract.

Tocopherols and tocotrienols represent the two subclasses within the vitamin E family of compounds. However, tocotrienols are significantly more potent than tocopherols in suppressing epidermal growth factor (EGF)-dependent normal mammary epithelial cell growth. EGF is a potent mitogen for normal mammary epithelial cells and an initial event in EGF-receptor mitogenic-signalling is protein kinase C (PKC) activation. Studies were conducted to determine if the antiproliferative effects of specific tocopherol and tocotrienol isoforms are associated with a reduction in EGF-receptor mitogenic signalling and/or PKC activation. Normal mammary epithelial cells isolated from midpregnant BALB/c mice were grown in primary culture, and maintained on serum-free media containing 10 ng/mL EGF as a mitogen, and treated with various doses (0–250 µm) of α-, γ-, or δ-tocopherol or α-, γ-, or δ-tocotrienol. Treatment with growth inhibitory doses of δ-tocopherol (100 µm), α-tocotrienol (50 µm), or γ- or δ-tocotrienol (10 µm) did not affect EGF-receptor levels, EGF-induced EGF-receptor tyrosine kinase activity, or total intracellular levels of PKCα. However, these treatments were found to inhibit EGF-induced PKCα activation as determined by its translocation from the cytosolic to membrane fraction. Treatment with 250 µmα- or γ-tocopherol had no affect on EGF-receptor mitogenic signalling or cell growth. These findings demonstrate that the inhibitory effects of specific tocopherol and tocotrienol isoforms on EGF-dependent normal mammary epithelial cell mitogenesis occurs downstream from the EGF-receptor and appears to be mediated, at least in part, by a reduction in PKCα activation.

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