Downregulation of autophagy by Bcl-2 promotes MCF7 breast cancer cell growth independent of its inhibition of apoptosis

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The anti-apoptotic Bcl-2 protein, which confers oncogenic transformation and drug resistance in most human cancers, including breast cancer, has recently been shown to effectively counteract autophagy by directly targeting Beclin1, an essential autophagy mediator and tumor suppressor. However, it remains unknown whether autophagy inhibition contributes to Bcl-2-mediated oncogenesis. Here, by using a loss-of-function mutagenesis study, we show that Bcl-2-mediated antagonism of autophagy has a critical role in enhancing the tumorigenic properties of MCF7 breast cancer cells independent of its anti-apoptosis activity. A Bcl-2 mutant defective in apoptosis inhibition but competent for autophagy suppression promotes MCF7 breast cancer cell growth in vitro and in vivo as efficiently as wild-type Bcl-2. The growth-promoting activity of this Bcl-2 mutant is strongly correlated with its suppression of Beclin1-dependent autophagy, leading to sustained p62 expression and increased DNA damage in xenograft tumors, which may directly contribute to tumorigenesis. Thus, the anti-autophagic property of Bcl-2 is a key feature of Bcl-2-mediated oncogenesis and may in some contexts, serve as an attractive target for breast and other cancer therapies. Cell Death and Differentiation (2011) 18, 452-464; doi:10.1038/cdd.2010.116; published online 1 October 2010
Publisher
NATURE PUBLISHING GROUP
Issue Date
2011-03
Language
English
Article Type
Article
Keywords

DEATH; FAMILY; TUMORIGENESIS; BECLIN-1; PROTEIN; LC3; HOMOLOG; DISEASE; MARKER; DOMAIN

Citation

CELL DEATH AND DIFFERENTIATION, v.18, no.3, pp.452 - 464

ISSN
1350-9047
DOI
10.1038/cdd.2010.116
URI
http://hdl.handle.net/10203/101390
Appears in Collection
BS-Journal Papers(저널논문)
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