BRCA1 negatively regulates formation of autophagic vacuoles in MCF-7 breast cancer cells

In recent years, the function of different tumour suppressors in the regulation of macroautophagy has been studied. We show here that BRCA1, unlike other tumour suppressors, negatively regulates formation of autophagosomes and lysosomal mass under conditions of both basal and enhanced autophagy. In...

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Bibliographic Details
Published in:Experimental cell research 2010-10, Vol.316 (16), p.2618-2629
Main Authors: Esteve, Juan M., Armengod, María Eugenia, Knecht, Erwin
Format: Article
Language:English
Subjects:
Antioxidants
Autophagy
Blotting, Western
BRCA1
BRCA1 Protein - physiology
Breast cancer
Breast Neoplasms - metabolism
Breast Neoplasms - pathology
Cellular biology
Female
Flow Cytometry
Humans
Lysosomes
Mitochondria
Mitochondria - metabolism
Reactive Oxygen Species - metabolism
Reverse Transcriptase Polymerase Chain Reaction
RNA, Messenger - genetics
RNA, Small Interfering - pharmacology
ROS
Tumor Cells, Cultured
Tumors
Vacuoles - metabolism
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Summary:In recent years, the function of different tumour suppressors in the regulation of macroautophagy has been studied. We show here that BRCA1, unlike other tumour suppressors, negatively regulates formation of autophagosomes and lysosomal mass under conditions of both basal and enhanced autophagy. In MCF-7 breast cancer cells, increased formation of autophagic vacuoles after inactivation of BRCA1 by siRNAs is associated with an increase in reactive oxygen species, such as superoxide anion and hydrogen peroxide. This allows one to propose an antioxidant function for BRCA1 and suggests that dysfunctional mitochondria and the generated reactive oxygen species excess could explain the increased macroautophagy observed in the absence of BRCA1. In addition, a quick decrease in BRCA1 levels occurs when MCF-7 cells are switched to a nutrient-poor environment that stimulates macroautophagy and that is also reminiscent of certain phases of tumour growth. Inhibition of BRCA1 synthesis has an important role in this reduction, while there are almost no changes in BRCA1 degradation by lysosomes and proteasomes. Therefore, BRCA1 produces macroautophagy inhibition by reducing the formation of autophagic vacuoles, and this, together with the other results presented here, shows new functional aspects of BRCA1 that could help to clarify the role of autophagy in cancer development.
ISSN:0014-4827
1090-2422
DOI:10.1016/j.yexcr.2010.06.019