Simvastatin inhibition of mevalonate pathway induces apoptosis in human breast cancer cells via activation of JNK/CHOP/DR5 signaling pathway |
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Authors: | Archana Gopalan Weiping Yu Bob G Sanders Kimberly Kline |
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Institution: | 1. Department of Nutritional Sciences/A2703, University of Texas at Austin, Austin, TX 78712, USA;2. School of Biological Sciences/C0900, University of Texas at Austin, Austin, TX 78712, USA |
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Abstract: | Simvastatin (SVA) was shown to up-regulate expression of death receptor-5 (DR5), CCAAT/enhancer binding protein homologous protein (CHOP) and phosphorylated c-Jun N-terminal kinase (pJNK) in human breast cancer cell lines. siRNA knockdown of DR5, CHOP or JNK significantly blocked SVA-induced apoptosis, demonstrating the importance of JNK/CHOP/DR5 signaling pathway in SVA-induced apoptosis. Exogenous addition of either mevalonate or geranylgeranyl pyrophosphate (GGPP) inhibited SVA activation of JNK/CHOP/DR5 pro-apoptotic pathway, indicating that activation of JNK/CHOP/DR5 pro-apoptotic pathway is dependent on SVA inhibition of 3-hydroxy-3-methylglutaryl Coenzyme A (HMG-CoA) reductase and its intermediate GGPP. Data provide novel insight into better understanding the anticancer mechanisms of SVA. |
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Keywords: | Apoptosis CCAAT/enhancer binding protein homologous protein (CHOP) c-Jun N-terminal kinase (JNK) Death receptor-5 (DR5) Human breast cancer cells Simvastatin (SVA) |
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