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 p21cip/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 p21cip/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.

There is increasing evidence that statins, which are widely used in lowering serum cholesterol and the incidence of cardiovascular diseases, also exhibits anti-tumour properties. The underlying mechanisms by which statins-induced cancer cell death, however, remain incompletely understood. In this study, we explored the anti-tumour mechanisms of a lipophilic statin, lovastatin, in MCF-7 breast cancer cells. Lovastatin inhibited cell proliferation and induced cell apoptosis. Lovastatin caused p21 elevation while reduced cyclin D1 and survivin levels. Lovastatin also increased p53 phosphorylation, acetylation and its reporter activities. Results from chromatin immunoprecipitation analysis showed that p53 binding to the survivin promoter region was increased, while Sp1 binding to the region was decreased, in MCF-7 cells after lovastatin exposure. These actions were associated with liver kinase B1 (LKB1), AMP-activated protein kinase (AMPK) and p38 mitogen-activated protein kinase (p38MAPK) activation. Lovastatin's enhancing effects on p53 activation, p21 elevation and survivin reduction were significantly reduced in the presence of p38MAPK signalling inhibitor. Furthermore, LKB1-AMPK signalling blockade abrogated lovastatin-induced p38MAPK and p53 phosphorylation. Together these results suggest that lovastatin may activate LKB1-AMPK-p38MAPK-p53-survivin cascade to cause MCF-7 cell death. The present study establishes, at least in part, the signalling cascade by which lovastatin induces breast cancer cell death. K E Y W O R D Sbreast cancer, liver kinase B1, lovastatin, p53, surviving Huang and Chyuan contributed equally to this work. | 1823HUANG et Al.

Growing evidence shows that hydroxamate-based compounds exhibit broad-spectrum pharmacological properties including anti-tumor activity. However, the precise mechanisms underlying hydroxamate derivative-induced cancer cell death remain incomplete understood. In this study, we explored the anti-tumor mechanisms of a novel aliphatic hydroxamate-based compound, WMJ-J-09, in FaDu head and neck squamous cell carcinoma (HNSCC) cells. WMJ-J-09 induced G2/M cell cycle arrest and apoptosis in FaDu cells. These actions were associated with liver kinase B1 (LKB1), AMP-activated protein kinase (AMPK) and p38 mitogen-activated protein kinase (p38MAPK) activation, transcription factor p63 phosphorylation, as well as modulation of p21 and survivin. LKB1-AMPK-p38MAPK signaling blockade reduced WMJ-J-09’s enhancing effects in p63 phosphorylation, p21 elevation and survivin reduction. Moreover, WMJ-J-09 caused an increase in α-tubulin acetylation and interfered with microtubule assembly. Furthermore, WMJ-J-09 suppressed the growth of subcutaneous FaDu xenografts in vivo. Taken together, WMJ-J-09-induced FaDu cell death may involve LKB1-AMPK-p38MAPK-p63-survivin signaling cascade. HDACs inhibition and disruption of microtubule assembly may also contribute to WMJ-J-09’s actions in FaDu cells. This study suggests that WMJ-J-09 may be a potential lead compound and warrant the clinical development in the treatment of HNSCC.