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Mevastatin induces apoptosis in HL60 cells dependently on decrease in phosphorylated ERK

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Abstract

Mevastatin which is an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme in cholesterol synthesis, suppress cell proliferation and induce apoptosis. However, the molecular mechanism of apoptosis induction is not well understood. So, in the present study, we attempted to clarify the mechanism by which mevastatin induces apoptosis in HL60 cells. It was found that mevastatin induced apoptosis. At that time, we observed an increase in caspase-3 activity and morphological fragmentation of the nuclei. The apoptosis induced by mevastatin was not inhibited by the addition of farnesyl pyrophosphate (FPP), squalene, ubiquinone, and isopentenyladenine, but was inhibited by the addition of geranylgeranyl pyrophosphate (GGPP). When we examined the survival signals at the time of apoptotic induction, we also observed that the administration of mevastatin had caused a remarkable decrease in the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2). However, other survival signals, such as nuclear factor kappa B (NF-κB), protein kinase B (Akt), and p38 mitogen-activated protein kinase (p38), exhibited no change. In addition, no quantitative change was observed in Bcl-2, which was an anti-apoptosis protein. It was also observed that apoptosis was induced when U0126, an MEK inhibitor, was added to the cells to inhibit ERK. These results suggested that mevastatin induced apoptosis when it inhibited GGPP biosynthesis and consequently decreased the level of phosphorylated ERK, which was a survival signal; moreover, at that time, there was no influence on NF-κB, Akt, p38, and Bcl-2. The results of this study also suggested that mevastatin could be used as an anticancer agent. (Mol Cell Biochem 269: 109–114, 2005)

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Authors and Affiliations

  1. Division of Pharmacotherapy, School of Pharmaceutical Sciences, Kinki University, 3-4-1 Kowakae, Higashi-Osaka, Japan

    Shozo Nishida, Masanobu Tsubaki, Yoshihiro Tanimori, Masasi Yanae & Yoshiki Fujii

  2. Division of Biopharmaceutics, School of Pharmaceutical Sciences, Kinki University, 3-4-1 Kowakae, Higashi-Osaka, Japan

    Masahiro Iwaki

  3. Department of Pharmacy, Nara Hospital, Kinki University School of Medicine, 1248-1, Otoda-cho, Ikoma-shi, Nara, Japan

    Hiroshi Matsuoka

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  1. Shozo Nishida
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  2. Hiroshi Matsuoka
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Correspondence to Shozo Nishida.

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Nishida, S., Matsuoka, H., Tsubaki, M. et al. Mevastatin induces apoptosis in HL60 cells dependently on decrease in phosphorylated ERK. Mol Cell Biochem 269, 109–114 (2005). https://doi.org/10.1007/s11010-005-3086-0

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  • DOI: https://doi.org/10.1007/s11010-005-3086-0

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