Statins affect human glioblastoma and other cancers through TGF-β inhibition

// Aizhen Xiao 1 , Breanna Brenneman 1 , Desiree Floyd 1 , Laurey Comeau 2 , Kelsey Spurio 1 , Inan Olmez 1 , Jeongwu Lee 3 , Ichiro Nakano 4 , Jakub Godlewski 5 , Agnieszka Bronisz 5 , Noritaka Kagaya 6 , Kazuo Shin-ya 6 and Benjamin Purow 1 1 Departments of Neurology, University of Virginia, Charlottesville, VA 22908, USA 2 Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, VA 22908, USA 3 Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA 4 Department of Neurosurgery, University of Alabama, Birmingham, AL 35233, USA 5 Department of Neurosurgery, Brigham and Women’s Hospital, Boston, MA 02115, USA 6 National Institute of Advanced Industrial Science and Technology (AIST), Tokyo 135-0064, Japan Correspondence to: Benjamin Purow, email: bwp5g@virginia.edu Keywords: statin; glioblastoma; TGF-beta; SMAD3; RhoA/ROCK Received: September 18, 2018     Accepted: February 09, 2019     Published: March 01, 2019 ABSTRACT The cholesterol-lowering statins have known anti-cancer effects, but the mechanisms and how to utilize statins in oncology have been unclear. We noted in the CellMiner database that statin activity against cancer lines correlated with higher expression of TGF-β target genes such as SERPINE1 and ZYX . This prompted us to assess whether statins affected TGF-β activity in glioblastoma (GBM), a cancer strongly influenced by TGF-β and in dire need of new therapeutic approaches. We noted that statins reduced TGF-β activity, cell viability and invasiveness, Rho/ROCK activity, phosphorylation and activity of the TGF-β mediator Smad3, and expression of TGF-β targets ZYX and SERPINE1 in GBM and GBM-initiating cell (GIC) lines. Statins were most potent against GBM, GIC, and other cancer cells with high TGF-β activity, and exogenous TGF-β further sensitized mesenchymal GICs to statins. Statin toxicity was rescued by addition of exogenous mevalonolactone or geranylgeranyl pyrophosphate, indicating that the observed effects reflected inhibition of HMG CoA-reductase by the statins. Simvastatin significantly inhibited the growth of subcutaneous GIC grafts and prolonged survival in GIC intracranially grafted mice. These results indicate where the statins might best be applied as adjunct therapies in oncology, against GBM and other cancers with high TGF-β activity, and have implications for other statin roles outside of oncology.