Abstract
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.
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Abbreviations
- Bcl-2:
-
B-cell lymphoma 2
- BH:
-
Bcl-2 homology
- MMP:
-
mitochondrial membrane permeabilization
- PI3K:
-
phosphatidylinositol 3-kinase
- γ-HV68:
-
γ-herpesvirus 68
- WT:
-
wild-type
- TM:
-
transmembrane
- Co-IP:
-
co-immunoprecipitation
- STS:
-
staurosporine
- TNFα:
-
tumor necrosis factor-alpha
- p62:
-
SQSTM1/sequestosome 1
- TUNEL:
-
terminal deoxynucleotidyl transferase dUTP nick end labeling
- UPR:
-
unfolded protein response
- IHC:
-
immunohistochemistry
- PARP:
-
poly(ADP-ribose) polymerase
- mTOR:
-
mammalian target of rapamycin
- FLIP:
-
FLICE-like inhibitory protein
- TSC1/TSC2:
-
tuberous sclerosis 1 and 2
- H&E:
-
hematoxylin/eosin
- HPF:
-
high-power fields
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Acknowledgements
This work was partly supported by U.S. Public Health Service Grants CA140964, AI083841, the Leukemia & Lymphoma Society of USA, the Wright Foundation, and the Baxter Foundation (C Liang), and CA82057, CA91819, CA31363, CA115284, AI073099, Fletcher Jones Foundation, Hastings Foundation, and Korean GRL Program K20815000001 (JUJ). X E has a Ruth L Krischstein National Research Service Award. We thank Drs. B Levine, MJ Hardwick, S Virgin, S Field, T Yoshimori, and Y Ohsumi for providing reagents, M Connole for FACS analysis, P Furcinitti for technical help in imaging, D Hauser and E Barron for performing electron microscopy, and L Young for immunohistochemistry analysis. Finally, we thank all the lab members for their support and discussions.
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Oh, S., E, X., Ni, D. et al. Downregulation of autophagy by Bcl-2 promotes MCF7 breast cancer cell growth independent of its inhibition of apoptosis. Cell Death Differ 18, 452–464 (2011). https://doi.org/10.1038/cdd.2010.116
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DOI: https://doi.org/10.1038/cdd.2010.116
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