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.
Highlights
The statins inhibit the HMG-CoA reductase enzyme and are among the most widely-prescribed drugs in the world for their cholesterol-lowering function
Online tools enable pattern comparisons across the datasets, and using these tools we noted that cancer cell line sensitivity to several statins in the compound library correlated with the expression of certain Transforming Growth Factor-beta (TGF-β) target genes and mesenchymal genes [19, 20]
Statins have widely varying toxicity to glioblastoma and other cancer cells Given the important roles of TGF-β in GBM and previous work on the statins in GBM, we focused on this cancer initially
Summary
The statins inhibit the HMG-CoA reductase enzyme and are among the most widely-prescribed drugs in the world for their cholesterol-lowering function. An additional effect on cancers has long been suspected, based in part on numerous studies that have shown decreased risk of death from various cancers in patients on statins. This remains unclear for glioblastoma (GBM), [1]. A few potential mechanisms for statin effects on cancer cells have been posited, including down-regulation of NF-κB, but no central mechanism has emerged [2]. Though prior reports have shown that statins can have anti-glioma effects and have linked them to components of the Transforming Growth Factor-beta (TGF-β) pathway [3,4,5,6,7,8,9,10], the statins have not previously been shown to potently inhibit TGF-β as their primary anti-cancer mechanism
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
