Skip to main content

Thank you for visiting nature.com. 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.

  • Article
  • Published:

Tumours with PI3K activation are resistant to dietary restriction

Nature volume 458, pages 725–731 (2009)Cite this article

An Author Correction to this article was published on 30 April 2020

This article has been updated

Abstract

Dietary restriction delays the incidence and decreases the growth of various types of tumours, but the mechanisms underlying the sensitivity of tumours to food restriction remain unknown. Here we show that certain human cancer cell lines, when grown as tumour xenografts in mice, are highly sensitive to the anti-growth effects of dietary restriction, whereas others are resistant. Cancer cells that form dietary-restriction-resistant tumours carry mutations that cause constitutive activation of the phosphatidylinositol-3-kinase (PI3K) pathway and in culture proliferate in the absence of insulin or insulin-like growth factor 1. Substitution of an activated mutant allele of PI3K with wild-type PI3K in otherwise isogenic cancer cells, or the restoration of PTEN expression in a PTEN-null cancer cell line, is sufficient to convert a dietary-restriction-resistant tumour into one that is dietary-restriction-sensitive. Dietary restriction does not affect a PTEN-null mouse model of prostate cancer, but it significantly decreases tumour burden in a mouse model of lung cancer lacking constitutive PI3K signalling. Thus, the PI3K pathway is an important determinant of the sensitivity of tumours to dietary restriction, and activating mutations in the pathway may influence the response of cancers to dietary restriction-mimetic therapies.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Human tumour xenografts display differential sensitivities to dietary restriction.
Figure 2: Constitutive PI3K activation correlates with tumour resistance to DR.
Figure 3: PIK3CA activating mutations or PTEN loss suppress tumour sensitivity to DR.
Figure 4: Effects of modulation of PI3K signalling on the apoptotic response of tumours to DR.
Figure 5: A KRAS mouse model of lung cancer, but not a PTEN-null model of prostate cancer, is sensitive to DR.

Similar content being viewed by others

Change history

  • 30 April 2020

    "An amendment to this paper has been published and can be accessed via a link at the top of the paper."

References

  1. Moreschi, C. Beziehung zwischen Ernahrung und Tumorwachstum. Zeitschrift f. Immunitätsforsch. Originale 2, 651–675 (1909)

    Google Scholar 

  2. Rous, P. The influence of diet on transplanted and spontaneous tumors. J. Exp. Med. 20, 351–413 (1914)

    Google Scholar 

  3. McCay, C. M., Crowell, M. F. & Maynard, L. A. The effect of retarded growth upon the length of life span and upon the ultimate body size. J. Nutr. 10, 63–79 (1935)

    Article  CAS  Google Scholar 

  4. Tannenbaum, A. & Silverstone, H. The influence of the degree of caloric restriction on the formation of skin tumors and hepatomas in mice. Cancer Res. 9, 724–727 (1949)

    CAS  PubMed  Google Scholar 

  5. Tannenbaum, A. & Silverstone, H. Effect of limited food intake on survival of mice bearing spontaneous mammary carcinoma and on the incidence of lung metastases. Cancer Res. 13, 532–536 (1953)

    CAS  PubMed  Google Scholar 

  6. Cheney, K. E. et al. Survival and disease patterns in C57BL/6J mice subjected to undernutrition. Exp. Gerontol. 15, 237–258 (1980)

    Article  CAS  Google Scholar 

  7. Weindruch, R. & Walford, R. L. Dietary restriction in mice beginning at 1 year of age: effect on life-span and spontaneous cancer incidence. Science 215, 1415–1418 (1982)

    Article  ADS  CAS  Google Scholar 

  8. Klurfeld, D. M., Welch, C. B., Davis, M. J. & Kritchevsky, D. Determination of degree of energy restriction necessary to reduce DMBA-induced mammary tumorigenesis in rats during the promotion phase. J. Nutr. 119, 286–291 (1989)

    Article  CAS  Google Scholar 

  9. Zhu, Z., Haegele, A. D. & Thompson, H. J. Effect of caloric restriction on pre-malignant and malignant stages of mammary carcinogenesis. Carcinogenesis 18, 1007–1012 (1997)

    Article  CAS  Google Scholar 

  10. Kritchevsky, D. Caloric restriction and cancer. J. Nutr. Sci. Vitaminol. (Tokyo) 47, 13–19 (2001)

    Article  CAS  Google Scholar 

  11. Thompson, H. J., Zhu, Z. & Jiang, W. Dietary energy restriction in breast cancer prevention. J. Mammary Gland Biol. Neoplasia 8, 133–142 (2003)

    Article  Google Scholar 

  12. Sell, C. Caloric restriction and insulin-like growth factors in aging and cancer. Horm. Metab. Res. 35, 705–711 (2003)

    Article  CAS  Google Scholar 

  13. Cheney, K. E. et al. The effect of dietary restriction of varying duration on survival, tumor patterns, immune function, and body temperature in B10C3F1 female mice. J. Gerontol. 38, 420–430 (1983)

    Article  CAS  Google Scholar 

  14. Pugh, T. D., Oberley, T. D. & Weindruch, R. Dietary intervention at middle age: caloric restriction but not dehydroepiandrosterone sulfate increases lifespan and lifetime cancer incidence in mice. Cancer Res. 59, 1642–1648 (1999)

    CAS  PubMed  Google Scholar 

  15. Ruggeri, B. A., Klurfeld, D. M., Kritchevsky, D. & Furlanetto, R. W. Caloric restriction and 7,12-dimethylbenz(a)anthracene-induced mammary tumor growth in rats: alterations in circulating insulin, insulin-like growth factors I and II, and epidermal growth factor. Cancer Res. 49, 4130–4134 (1989)

    CAS  PubMed  Google Scholar 

  16. Breese, C. R., Ingram, R. L. & Sonntag, W. E. Influence of age and long-term dietary restriction on plasma insulin-like growth factor-1 (IGF-1), IGF-1 gene expression, and IGF-1 binding proteins. J. Gerontol. 46, B180–B187 (1991)

    Article  CAS  Google Scholar 

  17. Miller, F. R., Santner, S. J., Tait, L. & Dawson, P. J. MCF10DCIS.com xenograft model of human comedo ductal carcinoma in situ . J. Natl. Cancer Inst. 92, 1185–1186 (2000)

    Article  CAS  Google Scholar 

  18. Manning, B. D. & Cantley, L. C. AKT/PKB signaling: navigating downstream. Cell 129, 1261–1274 (2007)

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  20. Salmena, L., Carracedo, A. & Pandolfi, P. P. Tenets of PTEN tumor suppression. Cell 133, 403–414 (2008)

    Article  CAS  Google Scholar 

  21. Samuels, Y. et al. Mutant PIK3CA promotes cell growth and invasion of human cancer cells. Cancer Cell 7, 561–573 (2005)

    Article  CAS  Google Scholar 

  22. Kang, S., Bader, A. G. & Vogt, P. K. Phosphatidylinositol 3-kinase mutations identified in human cancer are oncogenic. Proc. Natl Acad. Sci. USA 102, 802–807 (2005)

    Article  ADS  CAS  Google Scholar 

  23. Saal, L. H. et al. PIK3CA mutations correlate with hormone receptors, node metastasis, and ERBB2, and are mutually exclusive with PTEN loss in human breast carcinoma. Cancer Res. 65, 2554–2559 (2005)

    Article  CAS  Google Scholar 

  24. Zhao, J. J. et al. The oncogenic properties of mutant p110α and p110β phosphatidylinositol 3-kinases in human mammary epithelial cells. Proc. Natl Acad. Sci. USA 102, 18443–18448 (2005)

    Article  ADS  CAS  Google Scholar 

  25. Samuels, Y. et al. High frequency of mutations of the PIK3CA gene in human cancers. Science 304, 554 (2004)

    Article  CAS  Google Scholar 

  26. Cancer Cell Line Project. <http://www.sanger.ac.uk/genetics/CGP/CellLines/> (1992)

  27. Rodriguez-Viciana, P. et al. Phosphatidylinositol-3-OH kinase as a direct target of Ras. Nature 370, 527–532 (1994)

    Article  ADS  CAS  Google Scholar 

  28. Gupta, S. et al. Binding of ras to phosphoinositide 3-kinase p110α is required for ras-driven tumorigenesis in mice. Cell 129, 957–968 (2007)

    Article  CAS  Google Scholar 

  29. Calnan, D. R. & Brunet, A. The FoxO code. Oncogene 27, 2276–2288 (2008)

    Article  CAS  Google Scholar 

  30. Radu, A., Neubauer, V., Akagi, T., Hanafusa, H. & Georgescu, M. M. PTEN induces cell cycle arrest by decreasing the level and nuclear localization of cyclin D1. Mol. Cell. Biol. 23, 6139–6149 (2003)

    Article  CAS  Google Scholar 

  31. Wang, S. et al. Prostate-specific deletion of the murine Pten tumor suppressor gene leads to metastatic prostate cancer. Cancer Cell 4, 209–221 (2003)

    Article  CAS  Google Scholar 

  32. Johnson, L. et al. Somatic activation of the K-ras oncogene causes early onset lung cancer in mice. Nature 410, 1111–1116 (2001)

    Article  ADS  CAS  Google Scholar 

  33. Ventura, A. et al. Restoration of p53 function leads to tumour regression in vivo . Nature 445, 661–665 (2007)

    Article  CAS  Google Scholar 

  34. Fu, Z. & Tindall, D. J. FOXOs, cancer and regulation of apoptosis. Oncogene 27, 2312–2319 (2008)

    Article  CAS  Google Scholar 

  35. Kim, D. H. et al. mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery. Cell 110, 163–175 (2002)

    Article  CAS  Google Scholar 

  36. Kalaany, N. Y. et al. LXRs regulate the balance between fat storage and oxidation. Cell Metab. 1, 231–244 (2005)

    Article  CAS  Google Scholar 

  37. Wapnir, I. L., Wartenberg, D. E. & Greco, R. S. Three dimensional staging of breast cancer. Breast Cancer Res. Treat. 41, 15–19 (1996)

    Article  CAS  Google Scholar 

  38. Carpenter, A. E. et al. CellProfiler: image analysis software for identifying and quantifying cell phenotypes. Genome Biol. 7, R100 (2006)

    Article  Google Scholar 

  39. Lamprecht, M. R., Sabatini, D. M. & Carpenter, A. E. CellProfiler: free, versatile software for automated biological image analysis. Biotechniques 42, 71–75 (2007)

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank B. Vogelstein for providing the isogenic DLD-1 cell lines and M. M. Georgescu for the doxycycline-inducible U87-MG cell line; T. Jacks for the KRAS LA2; p53 LSL/WT mice and H. Wu for the Pb-Cre; PTEN L/L mice; F. Reinhardt for assistance with animal experiments; R. Bronson for histological analysis; the Histology Facility at the Koch Institute for Integrative Cancer Research and the Histology Core Laboratory at MIT for assistance with sectioning and immunohistochemistry; the Imaging Platform at the Broad Institute for assistance with image analysis; R. Weinberg, D. Guertin, Y. Chudnovsky and Y. Sancak for critical reading of the manuscript; and members of the Sabatini and Weinberg laboratories for support and discussions. This research is supported by the Alexander and Margaret Stewart Trust Award, the David H. Koch Cancer Research Award and National Institutes of Health grants R01 AI04389 and R01 CA129105. D.M.S. is an investigator of the Howard Hughes Medical Institute.

Author Contributions D.M.S. and N.Y.K. conceived the project and designed the experiments. N.Y.K. performed the experiments. The manuscript was written by N.Y.K. and edited by D.M.S.

Author information

Authors and Affiliations

  1. Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, Massachusetts 02142, USA ,

    Nada Y. Kalaany & David M. Sabatini

  2. Department of Biology, Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA,

    Nada Y. Kalaany & David M. Sabatini

  3. Koch Institute for Integrative Cancer Research at MIT, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA ,

    Nada Y. Kalaany & David M. Sabatini

  4. Broad Institute, Seven Cambridge Center, Cambridge, Massachusetts 02142, USA ,

    David M. Sabatini

Authors
  1. Nada Y. Kalaany
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. David M. Sabatini
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to David M. Sabatini.

Supplementary information

Supplementary Information

This file contains a Supplementary Discussion, Supplementary References and Supplementary Figures 1-4 with Legends (PDF 4035 kb)

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kalaany, N., Sabatini, D. Tumours with PI3K activation are resistant to dietary restriction. Nature 458, 725–731 (2009). https://doi.org/10.1038/nature07782

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature07782

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing