Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Molecular Diagnostics

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

A Correction to this article was published on 10 May 2021

This article has been updated



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.

This is a preview of subscription content, access via your institution

Access options

Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

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.

Change history


  1. Bardou, M., Barkun, A. & Martel, M. Effect of statin therapy on colorectal cancer. Gut 59, 1572–1585 (2010).

    CAS  PubMed  Google Scholar 

  2. Segnan, N., Senore, C., Andreoni, B., Arrigoni, A., Bisanti, L., Cardelli, A. et al. Randomized trial of different screening strategies for colorectal cancer: patient response and detection rates. J. Natl Cancer Inst. 97, 347–357 (2005).

    PubMed  Google Scholar 

  3. U. S. Preventive Services Task Force, Bibbins-Domingo, K., Grossman, D. C., Curry, S. J., Davidson, K. W., Epling, J. W. et al. Screening for colorectal cancer: US Preventive Services Task Force Recommendation Statement. JAMA 315, 2564–2575 (2016).

  4. Doubeni, C. A., Corley, D. A., Quinn, V. P., Jensen, C. D., Zauber, A. G., Goodman, M. et al. Effectiveness of screening colonoscopy in reducing the risk of death from right and left colon cancer: a large community-based study. Gut 67, 291–298 (2018).

    PubMed  Google Scholar 

  5. Jacobs, R. J., Kodach, L. L. & Hardwick, J. C. H. The potential of statins for individualized colorectal cancer chemoprevention. Curr. Drug Targets 12, 1903–1908 (2011).

    CAS  PubMed  Google Scholar 

  6. Arber, N. & Levin, B. Chemoprevention of colorectal neoplasia: the potential for personalized medicine. Gastroenterology 134, 1224–1237 (2008).

    CAS  PubMed  Google Scholar 

  7. Poynter, J. N., Gruber, S. B., Higgins, P. D. R., Almog, R., Bonner, J. D., Rennert, H. S. et al. Statins and the risk of colorectal cancer. N. Engl. J. Med. 352, 2184–2192 (2005).

    CAS  PubMed  Google Scholar 

  8. Graaf, M. R., Beiderbeck, A. B., Egberts, A. C. G., Richel, D. J. & Guchelaar, H.-J. The risk of cancer in users of statins. J. Clin. Oncol. 22, 2388–2394 (2004).

    CAS  PubMed  Google Scholar 

  9. Mamtani, R., Lewis, J. D., Scott, F. I., Ahmad, T., Goldberg, D. S., Datta, J. et al. Disentangling the association between statins, cholesterol, and colorectal cancer: a nested case-control study. PLoS Med. 13, e1002007 (2016).

    PubMed  PubMed Central  Google Scholar 

  10. Lytras, T., Nikolopoulos, G. & Bonovas, S. Statins and the risk of colorectal cancer: an updated systematic review and meta-analysis of 40 studies. World J. Gastroenterol. 20, 1858–1870 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Nissen, S. E., Tuzcu, E. M., Schoenhagen, P., Crowe, T., Sasiela, W. J., Tsai, J. et al. Statin therapy, LDL cholesterol, C-reactive protein, and coronary artery disease. N. Engl. J. Med. 352, 29–38 (2005).

    CAS  PubMed  Google Scholar 

  12. Downs, J. R., Clearfield, M., Weis, S., Whitney, E., Shapiro, D. R., Beere, P. A. et al. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study. JAMA 279, 1615–1622 (1998).

    CAS  PubMed  Google Scholar 

  13. Egan, A. & Colman, E. Weighing the benefits of high-dose simvastatin against the risk of myopathy. N. Engl. J. Med. 365, 285–287 (2011).

    CAS  PubMed  Google Scholar 

  14. Gazzerro, P., Proto, M. C., Gangemi, G., Malfitano, A. M., Ciaglia, E., Pisanti, S. et al. Pharmacological actions of statins: a critical appraisal in the management of cancer. Pharmacol. Rev. 64, 102–146 (2012).

    CAS  PubMed  Google Scholar 

  15. Kodach, L. L., Bleuming, S. A., Peppelenbosch, M. P., Hommes, D. W., van den Brink, G. R. & Hardwick, J. C. H. The effect of statins in colorectal cancer is mediated through the bone morphogenetic protein pathway. Gastroenterology 133, 1272–1281 (2007).

    CAS  PubMed  Google Scholar 

  16. Kodach, L. L., Jacobs, R. J., Voorneveld, P. W., Wildenberg, M. E., Verspaget, H. W., van Wezel, T. et al. Statins augment the chemosensitivity of colorectal cancer cells inducing epigenetic reprogramming and reducing colorectal cancer cell “stemness” via the bone morphogenetic protein pathway. Gut 60, 1544–1553 (2011).

    CAS  PubMed  Google Scholar 

  17. Voorneveld, P. W., Reimers, M. S., Bastiaannet, E., Jacobs, R. J., van Eijk, R., Zanders, M. M. J. et al. Statin use after diagnosis of colon cancer and patient survival. Gastroenterology 153, 470.e4–479.e4 (2017).

    Google Scholar 

  18. Demierre, M.-F., Higgins, P. D. R., Gruber, S. B., Hawk, E. & Lippman, S. M. Statins and cancer prevention. Nat. Rev. Cancer 5, 930–942 (2005).

    CAS  PubMed  Google Scholar 

  19. Guruswamy, S. & Rao, C. V. Multi-target approaches in colon cancer chemoprevention based on systems biology of tumor cell-signaling. Gene Regul. Syst. Biol. 2, 163–176 (2008).

    CAS  Google Scholar 

  20. Johnson, S. A. & Hunter, T. Kinomics: methods for deciphering the kinome. Nat. Methods 2, 17–25 (2005).

    CAS  PubMed  Google Scholar 

  21. Hazen, A. L., Diks, S. H., Wahle, J. A., Fuhler, G. M., Peppelenbosch, M. P. & Kerr, W. G. Major remodelling of the murine stem cell kinome following differentiation in the hematopoietic compartment. J. Proteome Res. 10, 3542–3550 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Diks, S. H., Kok, K., O’Toole, T., Hommes, D. W., van Dijken, P., Joore, J. et al. Kinome profiling for studying lipopolysaccharide signal transduction in human peripheral blood mononuclear cells. J. Biol. Chem. 279, 49206–49213 (2004).

    CAS  PubMed  Google Scholar 

  23. Wu, D., Sylvester, J. E., Parker, L. L., Zhou, G. & Kron, S. J. Peptide reporters of kinase activity in whole cell lysates. Biopolymers 94, 475–486 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Löwenberg, M., Tuynman, J., Scheffer, M., Verhaar, A., Vermeulen, L., van Deventer, S. et al. Kinome analysis reveals nongenomic glucocorticoid receptor-dependent inhibition of insulin signaling. Endocrinology 147, 3555–3562 (2006).

    PubMed  Google Scholar 

  25. Johnson, S. C. Hierarchical clustering schemes. Psychometrika 32, 241–254 (1967).

    CAS  PubMed  Google Scholar 

  26. Abramoff, M., Magalhaes, P. & Ram, S. Image processing with ImageJ. Biophotonics Int. 11, 36–42 (2004).

  27. Agarwal, B., Halmos, B., Feoktistov, A. S., Protiva, P., Ramey, W. G., Chen, M. et al. Mechanism of lovastatin-induced apoptosis in intestinal epithelial cells. Carcinogenesis 23, 521–528 (2002).

    CAS  PubMed  Google Scholar 

  28. Savas, S., Azorsa, D. O., Jarjanazi, H., Ibrahim-Zada, I., Gonzales, I. M., Arora, S. et al. NCI60 cancer cell line panel data and RNAi analysis help identify EAF2 as a modulator of simvastatin and lovastatin response in HCT-116 cells. PLoS ONE 6, e18306 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Cho, S.-J., Kim, J. S., Kim, J. M., Lee, J. Y., Jung, H. C. & Song, I. S. Simvastatin induces apoptosis in human colon cancer cells and in tumor xenografts, and attenuates colitis-associated colon cancer in mice. Int. J. Cancer 123, 951–957 (2008).

    CAS  PubMed  Google Scholar 

  30. Pan, H. Y., DeVault, A. R., Wang-Iverson, D., Ivashkiv, E., Swanson, B. N. & Sugerman, A. A. Comparative pharmacokinetics and pharmacodynamics of pravastatin and lovastatin. J. Clin. Pharmacol. 30, 1128–1135 (1990).

    CAS  PubMed  Google Scholar 

  31. Vazquez, F., Ramaswamy, S., Nakamura, N. & Sellers, W. R. Phosphorylation of the PTEN tail regulates protein stability and function. Mol. Cell Biol. 20, 5010–5018 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Rahdar, M., Inoue, T., Meyer, T., Zhang, J., Vazquez, F. & Devreotes, P. N. A phosphorylation-dependent intramolecular interaction regulates the membrane association and activity of the tumor suppressor PTEN. Proc. Natl Acad. Sci. USA 106, 480–485 (2009).

    CAS  PubMed  Google Scholar 

  33. Ross, A. H. & Gericke, A. Phosphorylation keeps PTEN phosphatase closed for business. Proc. Natl Acad. Sci. USA 106, 1297–1298 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Burgering, B. M. & Coffer, P. J. Protein kinase B (c-Akt) in phosphatidylinositol-3-OH kinase signal transduction. Nature 376, 599–602 (1995).

    CAS  PubMed  Google Scholar 

  35. Howe, J. R., Bair, J. L., Sayed, M. G., Anderson, M. E., Mitros, F. A., Petersen, G. M. et al. Germline mutations of the gene encoding bone morphogenetic protein receptor 1A in juvenile polyposis. Nat. Genet. 28, 184–187 (2001).

    CAS  PubMed  Google Scholar 

  36. Tenesa, A. & Dunlop, M. G. New insights into the aetiology of colorectal cancer from genome-wide association studies. Nat. Rev. Genet. 10, 353–358 (2009).

    CAS  PubMed  Google Scholar 

  37. Zhou, X. P., Woodford-Richens, K., Lehtonen, R., Kurose, K., Aldred, M., Hampel, H. et al. Germline mutations in BMPR1A/ALK3 cause a subset of cases of juvenile polyposis syndrome and of Cowden and Bannayan-Riley-Ruvalcaba syndromes. Am. J. Hum. Genet. 69, 704–711 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Waite, K. A. & Eng, C. BMP2 exposure results in decreased PTEN protein degradation and increased PTEN levels. Hum. Mol. Genet. 12, 679–684 (2003).

    CAS  PubMed  Google Scholar 

  39. Zimmerman, L. B., De Jesús-Escobar, J. M. & Harland, R. M. The Spemann organizer signal noggin binds and inactivates bone morphogenetic protein 4. Cell 86, 599–606 (1996).

    CAS  PubMed  Google Scholar 

  40. Kobielak, K., Stokes, N., de la Cruz, J., Polak, L. & Fuchs, E. Loss of a quiescent niche but not follicle stem cells in the absence of bone morphogenetic protein signaling. Proc. Natl Acad. Sci. USA 104, 10063–10068 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. He, X. C., Zhang, J., Tong, W.-G., Tawfik, O., Ross, J., Scoville, D. H. et al. BMP signaling inhibits intestinal stem cell self-renewal through suppression of Wnt-beta-catenin signaling. Nat. Genet. 36, 1117–1121 (2004).

    CAS  PubMed  Google Scholar 

  42. Stratton, M. R., Campbell, P. J. & Futreal, P. A. The cancer genome. Nature 458, 719–724 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Chan, A. T., Ogino, S. & Fuchs, C. S. Aspirin and the risk of colorectal cancer in relation to the expression of COX-2. N. Engl. J. Med. 356, 2131–2142 (2007).

    CAS  PubMed  Google Scholar 

  44. Liao, X., Morikawa, T., Lochhead, P., Imamura, Y., Kuchiba, A., Yamauchi, M. et al. Prognostic role of PIK3CA mutation in colorectal cancer: cohort study and literature review. Clin. Cancer Res. 18, 2257–2268 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Din, F. V. N., Valanciute, A., Houde, V. P., Zibrova, D., Green, K. A., Sakamoto, K. et al. Aspirin inhibits mTOR signaling, activates AMP-activated protein kinase, and induces autophagy in colorectal cancer cells. Gastroenterology 142, 1504.e3–1515.e3 (2012).

    Google Scholar 

  46. Engelman, J. A., Luo, J. & Cantley, L. C. The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism. Nat. Rev. Genet. 7, 606–619 (2006).

    CAS  PubMed  Google Scholar 

  47. Roudier, E., Mistafa, O. & Stenius, U. Statins induce mammalian target of rapamycin (mTOR)-mediated inhibition of Akt signaling and sensitize p53-deficient cells to cytostatic drugs. Mol. Cancer Ther. 5, 2706–2715 (2006).

    CAS  PubMed  Google Scholar 

  48. Holzer, T. R., Fulford, A. D., Arkins, A. M., Grondin, J. M., Mundy, C. W., Nasir, A. et al. Ischemic time impacts biological integrity of phospho-proteins in PI3K/Akt, Erk/MAPK, and p38 MAPK signaling networks. Anticancer Res. 31, 2073–2081 (2011).

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations



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 (

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.

Additional information

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.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

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).

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:


Quick links