Epidemiological studies and meta-analyses show an association between statin use and a reduced incidence of colorectal cancer (CRC). We have shown that statins act on CRC through bone morphogenetic protein (BMP) signalling, but the exact cellular targets and underlying mechanism of statin action remain elusive. In this study, we set out to assess the influence of statins on global cancer cell signalling by performing an array-based kinase assay using immobilised kinase substrates spanning the entire human kinome.
CRC cells with or without Lovastatin treatment were used for kinome analysis. Findings on kinome arrays were further confirmed by immunoblotting with activity-specific antibodies. Experiments in different CRC cell lines using immunoblotting, siRNA-mediated knockdown and treatment with specific BMP inhibitor Noggin were performed. The relevance of in vitro findings was confirmed in xenografts and in CRC patients treated with Simvastatin.
Kinome analysis can distinguish between non-specific, toxic effects caused by 10 µM of Lovastatin and specific effects on cell signalling caused by 2 µM Lovastatin. Statins induce upregulation of PTEN activity leading to downregulation of the PI3K/Akt/mTOR signalling. Treatment of cells with the specific BMP inhibitor Noggin as well as PTEN knockdown and transfection of cells with a constitutively active form of AKT abolishes the effect of Lovastatin on mTOR phosphorylation. Experiments in xenografts and in patients treated with Simvastatin confirm statin-mediated BMP pathway activation, activation of PTEN and downregulation of mTOR signalling.
Statins induce BMP-specific activation of PTEN and inhibition of PI3K/Akt/mTOR signalling in CRC.
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Ethics approval and consent to participate
The study was performed in accordance with the Declaration of Helsinki. The patient study was approved by the LUMC Medical Ethics Committee. Patients provided their informed consent for participation. The animal study was approved by the AMC Animal Experiments Committee.
Data are available upon request from the corresponding author (firstname.lastname@example.org).
The authors declare no competing interests.
R.J.J., L.L.K. and J.H. are funded by the Dutch Cancer Society (KWF). P.W.V. and J.H. are funded by the Netherlands Digestive Diseases foundation.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
The original online version of this article was revised: Lucas J. A. C. Hawinkels should be Lukas J. A. C. Hawinkels.
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Ouahoud, S., Jacobs, R.J., Peppelenbosch, M.P. et al. Kinome-wide analysis of the effect of statins in colorectal cancer. Br J Cancer 124, 1978–1987 (2021). https://doi.org/10.1038/s41416-021-01318-9