Simvastatin inhibition of mevalonate pathway induces apoptosis in human breast cancer cells via activation of JNK/CHOP/DR5 signaling pathway

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.

► Lipophilic statin, simvastatin, triggers apoptosis in human breast cancer cells via JNK/CHOP/DR5 dependent signaling.
► Simvastatin blockage of mevalonate and geranylgeranyl pyrophosphate is critical for pro-death effect.
► Death Receptor 5 protein levels are upregulated by simvastatin and necessary for simvastatin-induced apoptosis.