Downregulation of autophagy by Bcl-2 promotes MCF7 breast cancer cell growth independent of its inhibition of apoptosis.
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.
Oh
S
S
Department of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, CA 90033, USA.
Xiaofei
E
E
Ni
D
D
Pirooz
S D
SD
Lee
J-Y
JY
Lee
D
D
Zhao
Z
Z
Lee
S
S
Lee
H
H
Ku
B
B
Kowalik
T
T
Martin
S E
SE
Oh
B-H
BH
Jung
J U
JU
Liang
C
C
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001343:Autophagy; D000071186:Beclin-1; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology* / Q000648:ultrastructure; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000378:metabolism / Q000473:pathology; D004249:DNA Damage; D015536:Down-Regulation; D005260:Female; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D050505:Mutant Proteins / Q000378:metabolism; D041681:NIH 3T3 Cells; D011485:Protein Binding; D017433:Protein Structure, Secondary; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000737:chemistry / Q000378:metabolism*; D000071456:Sequestosome-1 Protein; D013329:Structure-Activity Relationship; D023041:Xenograft Model Antitumor Assays
D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; D006360:Heat-Shock Proteins; D008565:Membrane Proteins; D050505:Mutant Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D000071456:Sequestosome-1 Protein; C101343:Sqstm1 protein, mouse