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

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 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.

Lovastatin‐mediated MCF‐7 cancer cell death involves LKB1‐AMPK‐p38MAPK‐p53‐survivin signalling cascade

“…13,14,20,42 We thus determined whether lovastatin modulates the expression of these proteins in MCF-7 cells. In addition, survivin reduction causes cell cycle arrest and death in a variety of cancer cells.…”

“…14,15 As p53 is an essential and negative regulator of survivin, pharmacological approaches targeting p53-survivin signalling might be a promising therapeutic strategy for intervention of cancer. 14,15 As p53 is an essential and negative regulator of survivin, pharmacological approaches targeting p53-survivin signalling might be a promising therapeutic strategy for intervention of cancer.…”

“…Statins, the 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, are widely used in treating hyperlipidemia and lowering risk of cardiovascular disease or its related complications. 14,[20][21][22] In experimental animal models, statins are capable of suppressing angiogenesis, tumour invasion and metastasis. 18,19 Statins caused cell cycle arrest or apoptosis in various cancer types such as colorectal cancer, head and neck squamous cell carcinoma (HNSCC), lung cancer and breast cancer.…”

“…Recent studies demonstrated that stains usage reduces breast cancer-specific mortality in patients with breast cancer. 38 Moreover, several signalling cascades including p21 induction 14,20 and survivin reduction 11 seem to be involved in lovastatin-induced MCF-7 cell death. Induction of oxidative stress, 36 stimulation of inducible nitric oxide synthase (iNOS) 35 or alterations of Bax and Bcl-2 levels 37 has been explored as a possible cause of statins' cytotoxicity in MCF-7 breast cancer cells.…”

The Anticancer Activity of Cetraria Islandica (L.) Ach in Breast Cancer Cells Through Crosstalk of Ampk-α1 and Erk1/2 Signalling

“…AMPK associated with MAPK to trigger to or cell survival or death pathway (Hadrich et al, 2016). ERK½has a significant role in cell survival, but P38 plays acrucial role in cell death (Yan et al, 2016;Yen et al, 2016). Phosphorylated AMPK has been reported to decrease PPAR-γ.…”