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  • Title: Apoptosis induction by a dopaminergic neurotoxin, 1-methyl-4-phenylpyridinium ion (MPP(+)), and inhibition by epidermal growth factor in GH3 cells.
    Author: Yoshinaga N, Murayama T, Nomura Y.
    Journal: Biochem Pharmacol; 2000 Jul 01; 60(1):111-20. PubMed ID: 10807952.
    Abstract:
    A dopaminergic neurotoxin, 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine (MPTP), can induce dopaminergic denervation and Parkinsonism in humans. The active metabolite of MPTP is the 1-methyl-4-phenylpyridinium ion (MPP(+)). Previously we reported that MPP(+) is incorporated via the dopamine transport system and causes delayed cell death in GH3 cells, a clonal strain from the rat anterior pituitary. In this study, we investigated whether MPP(+) induces apoptosis. GH3 cells cultured with MPP(+) exhibited DNA laddering and fragmentation in a time- and concentration-dependent manner. The effect of MPP(+) was inhibited in GH3 cells treated with a pan-caspase inhibitor (100 microM ZVAD-fmk), an antioxidant (25 mM N-acetyl-l-cysteine), or epidermal growth factor (EGF; 50 ng/mL). Because EGF stimulated tyrosine phosphorylation of the EGF receptor and tyrphostin AG1478 [4-(3-chloroanilino)-6,7-dimethoxyquinazoline; 5 microM, a specific inhibitor of EGF receptor kinase] abolished EGF inhibition, involvement of EGF receptor kinase is assumed. Protein kinase C-dependent processes and Bcl-2 protein expression were shown not to be involved in EGF inhibition. MPP(+) increased cytochrome c immunoreactivity in cytosolic fractions in GH3 cells. The addition of 200 microM MPP(+) to isolated mitochondrial fractions from GH3 cells stimulated the release of a 13-kDa protein that cross-reacted with anti-cytochrome c antibody. The release was inhibited in EGF-treated GH3 cells. Our findings demonstrated that (i) MPP(+) induces apoptosis of GH3 cells via cytochrome c release and caspase activation, and (ii) apoptosis by MPP(+) can be blocked by N-acetyl-l-cysteine or EGF treatment.
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