Molecular and functional interactions between AKT and SOX2 in breast carcinoma
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Thorsten Schaefer1,*, Hui Wang1,2,*, Perihan Mir2, Martina Konantz1, Tamara C. Pereboom1, Anna M. Paczulla1, Britta Merz3, Tanja Fehm4, Sven Perner5, Oliver C. Rothfuss3, Lothar Kanz2, Klaus Schulze-Osthoff3,6, Claudia Lengerke1,2,7
1Department of Biomedicine, University Hospital Basel, Basel, Switzerland
2Department of Internal Medicine II, University Hospital Tuebingen, Tuebingen, Germany
3Interfaculty Institute of Biochemistry, University of Tuebingen, Tuebingen, Germany
4Women's Hospital, University Hospital Duesseldorf, Duesseldorf, Germany
5Institute of Pathology, University of Luebeck, Luebeck, Germany
6German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany
7Clinic for Hematology, University Hospital Basel, Basel, Switzerland
*These authors have contributed equally to this work
Claudia Lengerke, e-mail: email@example.com
Keywords: SOX2, AKT, breast carcinoma, cancer stem cells, clonogenicity
Received: August 16, 2015 Accepted: October 10, 2015 Published: October 20, 2015
The transcription factor SOX2 is a key regulator of pluripotency in embryonic stem cells and plays important roles in early organogenesis. Recently, SOX2 expression was documented in various cancers and suggested as a cancer stem cell (CSC) marker. Here we identify the Ser/Thr-kinase AKT as an upstream regulator of SOX2 protein turnover in breast carcinoma (BC). SOX2 and pAKT are co-expressed and co-regulated in breast CSCs and depletion of either reduces clonogenicity. Ectopic SOX2 expression restores clonogenicity and in vivo tumorigenicity of AKT-inhibited cells, suggesting that SOX2 acts as a functional downstream AKT target. Mechanistically, we show that AKT physically interacts with the SOX2 protein to modulate its subcellular distribution. AKT kinase inhibition results in enhanced cytoplasmic retention of SOX2, presumably via impaired nuclear import, and in successive cytoplasmic proteasomal degradation of the protein. In line, blockade of either nuclear transport or proteasomal degradation rescues SOX2 expression in AKT-inhibited BC cells. Finally, AKT inhibitors efficiently suppress the growth of SOX2-expressing putative cancer stem cells, whereas conventional chemotherapeutics select for this population. Together, our results suggest the AKT/SOX2 molecular axis as a regulator of BC clonogenicity and AKT inhibitors as promising drugs for the treatment of SOX2-positive BC.
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