Open Access

Phosphorylation of eIF2α attenuates statin-induced apoptosis by inhibiting the stabilization and translocation of p53 to the mitochondria

  • Authors:
    • Sang Kyu Lee
    • Young Sang Kim
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  • Published online on: January 23, 2013     https://doi.org/10.3892/ijo.2013.1792
  • Pages: 810-816
  • Copyright: © Lee et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].

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Abstract

Statins are effective cholesterol-lowering drugs that exert pleiotropic effects, including cytotoxicity to cancer cells. We previously reported that simvastatin triggered the mitochondrial apoptotic pathway in MethA fibrosarcoma cells, which was accompanied by the translocation of stabilized p53 to the mitochondria. In this study, we investigated whether statins induce the endoplasmic reticulum (ER) stress response and the mechanisms by which this response is linked to the stabilization of p53 and its translocation to the mitochondria. Statins induced typical ER stress-related proteins, such as BiP/78 kDa glucose-regulated protein (Grp78) and CCAAT/enhancer-binding protein homologous protein (CHOP), as well as the phosphorylation of protein kinase RNA-like endoplasmic reticulum kinase (PERK), eIF2α and JNK. The statin-induced phosphorylation of eIF2α and JNK was inhibited by supplementation with components of the mevalonate pathway, such as mevalonate, farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP). Salubrinal, an inhibitor of the dephosphorylation of eIF2α, suppressed the loss of mitochondrial membrane potential and the translocation of stabilized p53 and Bax to the mitochondria; however, SP600125, a JNK kinase inhibitor, did not exert this effect. Furthermore, the eIF2α knockdown sensitized cells to simvastatin-induced apoptosis and the overexpression of a non-phosphorylatable eIF2α-mutant [serine 51(Ser51)/alanine] enhanced the stabilization of p53 and its translocation to the mitochondria in response to simvastatin treatment. Taken together, these data indicate that eIF2α phosphorylation in the context of the ER stress response plays a role in cell survival by counteracting the p53-mediated mitochondrial apoptosis in response to statins.
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March 2013
Volume 42 Issue 3

Print ISSN: 1019-6439
Online ISSN:1791-2423

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Spandidos Publications style
Lee SK and Lee SK: Phosphorylation of eIF2α attenuates statin-induced apoptosis by inhibiting the stabilization and translocation of p53 to the mitochondria. Int J Oncol 42: 810-816, 2013
APA
Lee, S.K., & Lee, S.K. (2013). Phosphorylation of eIF2α attenuates statin-induced apoptosis by inhibiting the stabilization and translocation of p53 to the mitochondria. International Journal of Oncology, 42, 810-816. https://doi.org/10.3892/ijo.2013.1792
MLA
Lee, S. K., Kim, Y. S."Phosphorylation of eIF2α attenuates statin-induced apoptosis by inhibiting the stabilization and translocation of p53 to the mitochondria". International Journal of Oncology 42.3 (2013): 810-816.
Chicago
Lee, S. K., Kim, Y. S."Phosphorylation of eIF2α attenuates statin-induced apoptosis by inhibiting the stabilization and translocation of p53 to the mitochondria". International Journal of Oncology 42, no. 3 (2013): 810-816. https://doi.org/10.3892/ijo.2013.1792