Abstract
Simvastatin is currently one of the most common drugs for old patients with hyperlipidemia, hypercholesterolemia and atherosclerotic diseases by reducing cholesterol level and anti-lipid properties. Importantly, simvastatin has also been reported to have anti-tumor effect, but the underlying mechanism is largely unknown. We collected several human bladder samples and performed microarray. Data analysis suggested bladder cancer (BCa) was significantly associated with fatty acid/lipid metabolism via PPAR signalling pathway. We observed simvastatin did not trigger BCa cell apoptosis, but reduced cell proliferation in a dose- and time-dependent manner, accompanied by PPARγ-activation. Moreover, flow cytometry analysis indicated that simvastatin induced cell cycle arrest at G0/G1 phase, suggested by downregulation of CDK4/6 and Cyclin D1. Furthermore, simvastatin suppressed BCa cell metastasis by inhibiting EMT and affecting AKT/GSK3β. More importantly, we found that the cell cycle arrest at G0/G1 phase and the alterations of CDK4/6 and Cyclin D1 triggered by simvastatin could be recovered by PPARγ-antagonist (GW9662), whereas the treatment of PPARα-antagonist (GW6471) shown no significant effects on the BCa cells. Taken together, our study for the first time revealed that simvastatin inhibited bladder cancer cell proliferation and induced cell cycle arrest at G1/G0 phase via PPARγ signalling pathway.
Highlights
In the current study, our group has profiled several human Bladder cancer (BCa) tissues and normal bladder tissues to generate an novel pathway network[20], and the bioinformatic analysis promoted us to hypothesize that BCa might be associated with fatty acid and lipid metabolism via Peroxisome Proliferator-Activated Receptor (PPAR) signalling pathway
Gene ontology (GO) and Path-net analysis tools based on Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway revealed that the cell cycle, pathways in cancer and ErbB signalling pathway were significantly linked to BCa (Fig. 1b)
Fatty acid/lipid metabolism has been suggested to have be close related with bladder cancer via PPAR signalling pathway (Fig. 1b)
Summary
Our group has profiled several human BCa tissues and normal bladder tissues to generate an novel pathway network[20], and the bioinformatic analysis promoted us to hypothesize that BCa might be associated with fatty acid and lipid metabolism via Peroxisome Proliferator-Activated Receptor (PPAR) signalling pathway. PPARs are essential for the regulation of cellular differentiation, development, lipid metabolism and tumorigenesis[22,23] Their activation leads to altered expression of genes involved in cell metabolism, cell growth and stress response. Statins are the most common used and effective drugs for old patients with hyperlipidemia, hypercholesterolemia or atherosclerotic diseases[33,34]. In addition to their cholesterol reducing effects, increasing evidence from in vitro and in vivo studies has suggested that statins have anti-proliferative, pro-apoptotic and anti-metastasis effects in various types of cancer cells[35,36], including BCa cells. We aim to investigate the potential mechanism of the alterations in bladder cancer cells triggered by the treatment of simvastatin
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