title: Atorvastatin inhibits RhoC function and limits head and neck cancer metastasis.
abstract: OBJECTIVE
  RhoC oncogene is a well characterized marker of metastasis in a majority of invasive cancers, including HNSCC. Elevated RhoC expression has been found to be associated with distant metastasis. Statins are a class of drugs that are used to reduce cholesterol levels by inhibiting HMG-CoA reductase activity which in turns prevents mevalonate synthesis, which is a precursor for synthesis of cholesterol and prenylation. Interestingly, the proper function of Rho proteins depends on prenylation. Significantly, it has been reported that metastasis in human melanoma can be reduced by atorvastatin which inhibits RhoC activity by preventing its geranylgeranylation. Given that RhoC is a key oncogene involved in metastasis, we hypothesized Atorvastatin can reduce head and neck metastasis by inhibiting RhoC activity.
  
  
  METHODS
  In vitro and in vivo studies were carried out to evaluate the ability of Atorvastatin to inhibit RhoC function and HNSCC metastasis. Cell motility, proliferation, cell invasion, and colony formation assays were performed according to the standard protocols.
  
  
  RESULTS
  Atorvastatin treatment significantly reduced the active form of RhoC in vitro and diminished cell motility, invasion, proliferation and colony formation. Importantly, we observed a significant decrease in p-ERK1/2 and p-STAT3 in Atorvastatin treated cell lines. In vivo experiments revealed inhibition of angiogenesis and lung metastases with Atorvastatin therapy.
  
  
  CONCLUSIONS
  This study is the first of its kind to establish a potential role of Atorvastatin in head and neck cancer therapy. These findings suggest that Atorvastatin can be a potential low risk adjuvant therapy to minimize metastases in aggressive forms of HNSCC.
authors: Department of Otolaryngology-Head and Neck Surgery, The Ohio State University Wexner Medical Center, Columbus, OH, USA. Mozaffarul.Islam@osumc.edu
authors: Mozaffarul
authors: M
authors: Islam
authors: Smita
authors: S
authors: Sharma
authors: Bhavna
authors: B
authors: Kumar
authors: Theodoros N
authors: TN
authors: Teknos
mesh_terms: D000818:Animals; D000069059:Atorvastatin; D002294:Carcinoma, Squamous Cell / Q000473:pathology* / Q000503:physiopathology; D006258:Head and Neck Neoplasms / Q000473:pathology* / Q000503:physiopathology; D006538:Heptanoic Acids / Q000494:pharmacology*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D020935:MAP Kinase Signaling System; D051379:Mice; D009362:Neoplasm Metastasis / Q000517:prevention & control*; D010766:Phosphorylation; D011758:Pyrroles / Q000494:pharmacology*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000037:antagonists & inhibitors*; D000075024:rhoC GTP-Binding Protein
chemical_list: D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011758:Pyrroles; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D000069059:Atorvastatin; C066690:RHOC protein, human; D020741:rho GTP-Binding Proteins; D000075024:rhoC GTP-Binding Protein
keywords: Geranylation; HMG-COA reductase; Head and neck squamous cell carcinoma; Lung metastasis; RhoC
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