Lovastatin causes FaDu hypopharyngeal carcinoma cell death via AMPK-p63-survivin signaling cascade

Chia Sheng Yen, Jung Chien Chen, Yi Fang Chang, Ya Fen Hsu, Pei Ting Chiu, Ching Shiue, Yu Fan Chuang, George Ou, Ming Jen Hsu

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Abstract

Statins are used widely to lower serum cholesterol and the incidence of cardiovascular diseases. Growing evidence shows that statins also exhibit beneficial effects against cancers. In this study, we investigated the molecular mechanisms involved in lovastatin-induced cell death in Fadu hypopharyngeal carcinoma cells. Lovastatin caused cell cycle arrest and apoptosis in FaDu cells. Lovastatin increased p21 cip/Waf1 level while the survivin level was decreased in the presence of lovastatin. Survivin siRNA reduced cell viability and induced cell apoptosis in FaDu cells. Lovastatin induced phosphorylation of AMP-activated protein kinase (AMPK), p38 mitogen-activated protein kinase (MAPK) and transcription factor p63. Lovastatin also caused p63 acetylation and increased p63 binding to survivin promoter region in FaDu cells. AMPK-p38MAPK signaling blockade abrogated lovastatin-induced p63 phosphorylation. Lovastatin's enhancing effect on p63 acetylation was reduced in HDAC3- or HDAC4- transfected cells. Moreover, transfection of cells with AMPK dominant negative mutant (AMPK-DN), HDAC3, HDAC4 or p63 siRNA significantly reduced lovastatin's effects on p21 cip/Waf1 and survivin. Furthermore, lovastatin inhibited subcutaneous FaDu xenografts growth in vivo. Taken together, lovastatin may activate AMPK-p38MAPK-p63-survivin cascade to cause FaDu cell death. This study establishes, at least in part, the signaling cascade by which lovastatin induces hypopharyngeal carcinoma cell death.

Original languageEnglish
Article number25082
JournalScientific Reports
Volume6
DOIs
Publication statusPublished - Apr 28 2016

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Cite this

Yen, C. S., Chen, J. C., Chang, Y. F., Hsu, Y. F., Chiu, P. T., Shiue, C., Chuang, Y. F., Ou, G., & Hsu, M. J. (2016). Lovastatin causes FaDu hypopharyngeal carcinoma cell death via AMPK-p63-survivin signaling cascade. Scientific Reports, 6, [25082]. https://doi.org/10.1038/srep25082