Production of superoxide and dissipation of mitochondrial transmembrane potential by vitamin K2 trigger apoptosis in human ovarian cancer TYK-nu cells

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Abstract
We reported previously that vitamin K2 selectively induces apoptosis in human ovary cancer cells (TYK-nu cells) and pancreatic cancer cells (MIA PaCa-2 cells) through a mitochondrion-dependent pathway. In the present study, we examined the details of the mechanism of vitamin K2-induced apoptosis in TYK-nu cells. We found that superoxide (O2 •−) was produced by TYK-nu cells between 2 and 3 days after the start of treatment with vitamin K2, whereas it was produced within 30 min after the start of treatment with geranylgeraniol. The vitamin K2-induced apoptosis was inhibited by anti-oxidants, such as α-tocopherol, Tiron and N-acetyl-L-cysteine (NAC). Furthermore, both the production of superoxide and the induction of apoptosis by vitamin K2 were inhibited almost completely by cycloheximide, an inhibitor of protein synthesis, suggesting that the synthesis of enzymes for the production of superoxide might be required for these processes. In parallel with the production of superoxide, the mitochondrial transmembrane potential, as measured by staining with Mitotracker Red CMXRos, dissipated during treatment of TYK-nu cells with vitamin K2 for 3 days. The vitamin K2-induced depolarization of mitochondrial membranes was completely inhibited by α-tocopherol and, to a lesser extent, by Tiron and NAC. Since α-tocopherol reacts with oxygen radicals, such as superoxide, within the hydrophobic environment of the mitochondrial membrane, we postulate that vitamin K2-induced oxidative stress in mitochondria might damage mitochondrial membranes, with subsequent release of cytochrome c, the activation of procaspase 3 and, eventually, apoptosis.

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