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Colorectal carcinomas in mice lacking the catalytic subunit of PI(3)Kγ

Nature volume 406, pages 897–902 (2000)Cite this article

A Corrigendum to this article was published on 04 December 2003

Abstract

Phosphoinositide-3-OH kinases (PI(3)Ks) constitute a family of evolutionarily conserved lipid kinases that regulate a vast array of fundamental cellular responses, including proliferation, transformation, differentiation and protection from apoptosis1,2. PI(3)K-mediated activation of the cell survival kinase PKB/Akt, and negative regulation of PI(3)K signalling by the tumour suppressor PTEN (refs 3, 4) are key regulatory events in tumorigenesis5,6,7. Thus, a model has arisen that PI(3)Ks promote development of cancers. Here we report that genetic inactivation of the p110γ catalytic subunit of PI(3)Kγ (ref. 8) leads to development of invasive colorectal adenocarcinomas in mice. In humans, p110γ protein expression is lost in primary colorectal adenocarcinomas from patients and in colon cancer cell lines. Overexpression of wild-type or kinase-dead p110γ in human colon cancer cells with mutations of the tumour suppressors APC and p53 , or the oncogenes β-catenin and Ki-ras, suppressed tumorigenesis. Thus, loss of p110γ in mice leads to spontaneous, malignant epithelial tumours in the colorectum and p110γ can block the growth of human colon cancer cells.

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Figure 1: Formation of colorectal adenocarcinomas in p110γ-/- mice.
Figure 2: APC and β-catenin expression in neoplastic lesions.
Figure 3: Upregulation of cell-cycle molecules and increased proliferation in p110γ-/- tumours.
Figure 4: Decreased expression of p110γ protein in human colon cancer cell lines and primary colon cancers from patients.
Figure 5: Overexpression of p110γ suppresses in vitro colony formation and in vivo tumour growth of human colon cancer cell lines.

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Acknowledgements

We thank M. Saunders for scientific editing and J. Ho, K. Jazier, M. Crackower, A. Oliveira-dos-Santos, L. Zhang, N. Joza, C. Krawczyk, I. Kozieradzki, M. Cheng, R. Sarao, Y.-Y. Kong, M. Nghiem, Q. Liu, E. Griffith, R. Williams, C. Sirard, V. Stambulic, M. Reth, C. Potten, A. Nepren, H. Okada, Y. Jang, S. Pownall, D. Lacey and W. Boyle for reagents and helpful discussions. This work is supported by grants from Amgen, the National Cancer Institute of Canada and the Canadian Center of Excellence for Tumor Vaccination.

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Authors and Affiliations

  1. Amgen Institute, Ontario Cancer Institute, and the Departments of Medical Biophysics and Immunology, University of Toronto, 620 University Avenue, Toronto, M5G 2C1, Ontario, Canada

    Takehiko Sasaki, Junko Irie-Sasaki, Kurt Bachmaier, Akira Suzuki, Dennis Bouchard, Alexandra Ho, Tak W. Mak & Josef M. Penninger

  2. Department of Medical Biophysics and Department of Laboratory Medicine and Pathobiology, Ontario Cancer Institute University of Toronto, 610 University Avenue, Toronto, M5G 2M9, Ontario, Canada

    Jimmie E. Fata & Rama Khokha

  3. Department of Genetics and Genomic Biology, The Hospital for Sick Children, 555 University Avenue , Toronto, M5G 1X8, Ontario, Canada

    Martin Li & Stephen W. Scherer

  4. Centre for Cancer Genetics, Samuel Lunenfeld Research Institute, 600 University Avenue, Toronto, M5G 1X5, Ontario, Canada

    Mark Redston & Steven Gallinger

  5. The Babraham Institute, Babraham, Cambridge, CB2 4AT, UK

    Phillip T. Hawkins & Len Stephens

  6. Departments of Laboratory Medicine and Pathology, University of Toronto, 600 University Avenue, Toronto, M5G 1X5, Ontario, Canada

    Ming Tsao

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Correspondence to Josef M. Penninger.

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Sasaki, T., Irie-Sasaki, J., Horie, Y. et al. Colorectal carcinomas in mice lacking the catalytic subunit of PI(3)Kγ . Nature 406, 897–902 (2000). https://doi.org/10.1038/35022585

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