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Molecular Diagnostics

Kinome-wide analysis of the effect of statins in colorectal cancer

British Journal of Cancer volume 124, pages 1978–1987 (2021)Cite this article

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A Correction to this article was published on 10 May 2021

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Abstract

Background

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.

Methods

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.

Results

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.

Conclusions

Statins induce BMP-specific activation of PTEN and inhibition of PI3K/Akt/mTOR signalling in CRC.

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Fig. 1: HCT116 colon cancer cells were treated with different concentrations of Lovastatin (0, 0.2, 2 and 10 µM) and cell viability was assessed at different time points using MTT assays.
Fig. 2: Phosphoproteome changes in CRC cells after statin treatment.
Fig. 3: Signal transduction effects in CRC cells after statin treatment.
Fig. 4: Statins act through PTEN to inhibition AKT/mTOR.
Fig. 5: The effects of statin treatment in CRC cells on the AKT/mTOR pathway are BMP dependent.
Fig. 6: Statin treatment of patients and a xenograft mouse model.

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Author information

Authors and Affiliations

  1. Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, the Netherlands

    Sarah Ouahoud, Rutger J. Jacobs, Lukas J. A. C. Hawinkels, Philip W. Voorneveld & James C. H. Hardwick

  2. Department of Gastroenterology and Hepatology, Erasmus MC, Erasmus University Rotterdam, Rotterdam, the Netherlands

    Maikel P. Peppelenbosch & G. M. Fühler

  3. Tytgat Institute for Liver & Intestinal Research, Academic Medical Center, Amsterdam, the Netherlands

    Jarom Heijmans & Manon E. Wildenberg

  4. Department of Pediatric Oncology, University Medical Center Groningen, Groningen, the Netherlands

    Sander Diks

  5. Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, the Netherlands

    Manon E. Wildenberg

  6. Department of Pathology, Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands

    Liudmila L. Kodach

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Contributions

S.O.: designed and performed experiments, analysed data, wrote manuscript. M.P.P., S.D., G.M.F.: analysed kinome array. R.J.J., J.H., M.E.W., G.M.F.: performed experiments. L.J.A.C.H.: advised and facilitated. L.L.K.: designed experiments, analysed data, and supervised the project. P.W.V.: designed and performed experiments, analysed data, and wrote the manuscript. J.C.H.H.: designed experiments, analysed data, wrote manuscript, and supervised the project.

Corresponding author

Correspondence to Philip W. Voorneveld.

Ethics declarations

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 availability

Data are available upon request from the corresponding author (p.w.voorneveld@lumc.nl).

Competing interests

The authors declare no competing interests.

Funding information

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.

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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

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