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Induction of autophagy and inhibition of tumorigenesis by beclin 1

Nature volume 402, pages 672–676 (1999)Cite this article

Abstract

The process of autophagy, or bulk degradation of cellular proteins through an autophagosomic-lysosomal pathway1, is important in normal growth control and may be defective in tumour cells2. However, little is known about the genetic mediators of autophagy in mammalian cells or their role in tumour development. The mammalian gene encoding Beclin 1 (ref. 3), a novel Bcl-2-interacting, coiled-coil protein, has structural similarity to the yeast autophagy gene, apg6/vps30 (refs 4, 5), and is mono-allelically deleted in 40–75% of sporadic human breast cancers and ovarian cancers6. Here we show, using gene-transfer techniques, that beclin 1 promotes autophagy in autophagy-defective yeast with a targeted disruption of agp6/vps30, and in human MCF7 breast carcinoma cells. The autophagy-promoting activity of beclin 1 in MCF7 cells is associated with inhibition of MCF7 cellular proliferation, in vitro clonigenicity and tumorigenesis in nude mice. Furthermore, endogenous Beclin 1 protein expression is frequently low in human breast epithelial carcinoma cell lines and tissue, but is expressed ubiquitously at high levels in normal breast epithelia. Thus, beclin 1 is a mammalian autophagy gene that can inhibit tumorigenesis and is expressed at decreased levels in human breast carcinoma. These findings suggest that decreased expression of autophagy proteins may contribute to the development or progression of breast and other human malignancies.

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Figure 1: Complementation by beclin 1 of the yeast autophagy but not vacuolar protein sorting function of apg6/vps30.
Figure 2: Promotion of autophagy by enforced beclin 1 expression in human MCF7 breast carcinoma cells.
Figure 3: Effects of enforced beclin 1 expression on the growth properties and tumorigenicity of MCF7 cells.
Figure 4: Decrease in Beclin 1 protein expression in human breast carcinoma cell lines and tissue.

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Acknowledgements

We thank R. Rothstein and L. Pons for helpful discussions, and J. Kitajewski and R. Dalla-Favera for providing reagents. This work was supported by the NIH, the American Cancer Society, an Irma T. Hirschl Trust Award and an Elaine B. Lesser Award in Ovarian Cancer Research.

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Authors and Affiliations

  1. Department of Medicine,

    Xiao Huan Liang, Saadiya Jackson & Beth Levine

  2. Department of Pathology, Columbia University College of Physicians & Surgeons, New York, 10032, New York, USA

    Kristy Brown & Hanina Hibshoosh

  3. Surgeons,

    Kristy Brown & Hanina Hibshoosh

  4. Department of Clinical Biochemistry Cambridge Institute for Medical Research, Addenbrookes Hospital, Cambridge, CB2 2XY, UK

    Matthew Seaman

  5. Institute for Clinical Molecular Biology, GSF-National Research Center for Environment and Health, Munich, 81377, Germany

    Bettina Kempkes

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  1. Xiao Huan Liang
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Correspondence to Beth Levine.

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Liang, X., Jackson, S., Seaman, M. et al. Induction of autophagy and inhibition of tumorigenesis by beclin 1 . Nature 402, 672–676 (1999). https://doi.org/10.1038/45257

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