SLC5A8 (solute carrier gene family 5A, member 8) is a sodium-coupled transporter for monocarboxylates. Among its substrates are the HDAC (histone deacetylase) inhibitors butyrate, propionate and pyruvate. Expression of SLC5A8 is silenced in cancers via DNA methylation, and ectopic expression of SLC5A8 in cancer cells induces apoptosis in the presence of its substrates that are HDAC inhibitors. In the present study we show that ectopic expression of SLC5A8 in cancer cells translocates the anti-apoptotic protein survivin to the plasma membrane through protein–protein interaction resulting in depletion of nuclear survivin and also decreases cellular levels of survivin through inhibition of transcription. These SLC5A8-induced changes in the location and levels of survivin result in cell-cycle arrest, disruption of the chromosome passenger complex involved in mitosis, induction of apoptosis and enhancement in chemosensitivity. These effects are seen independently of the transport function of SLC5A8 and histone acetylation status of the cell; in the presence of pyruvate, a SLC5A8 substrate and also an HDAC inhibitor, these effects are amplified. Ectopic expression of SLC5A8 in the breast cancer cell line MB231 inhibits the ability of cells to form colonies in vitro and to form tumours in mouse xenografts in vivo. The suppression of survivin transcription occurs independently of HDAC inhibition, and the underlying mechanism is associated with decreased phosphorylation of STAT3 (signal transducer and activator of transcription 3). The observed effects are specific for survivin with no apparent changes in expression of other inhibitor-of-apoptosis proteins. The present study unravels a novel, hitherto unrecognized, mechanism for the tumour-suppressive role of a plasma membrane transporter independent of its transport function.
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Research Article|
January 24 2013
The plasma membrane transporter SLC5A8 suppresses tumour progression through depletion of survivin without involving its transport function
Veena Coothankandaswamy;
Veena Coothankandaswamy
1Department of Biochemistry and Molecular Biology, Medical College of Georgia, Georgia Health Sciences University, Augusta, GA 30912, U.S.A.
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Selvakumar Elangovan;
Selvakumar Elangovan
1Department of Biochemistry and Molecular Biology, Medical College of Georgia, Georgia Health Sciences University, Augusta, GA 30912, U.S.A.
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Nagendra Singh;
Nagendra Singh
1Department of Biochemistry and Molecular Biology, Medical College of Georgia, Georgia Health Sciences University, Augusta, GA 30912, U.S.A.
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Puttur D. Prasad;
Puttur D. Prasad
1Department of Biochemistry and Molecular Biology, Medical College of Georgia, Georgia Health Sciences University, Augusta, GA 30912, U.S.A.
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Muthusamy Thangaraju;
Muthusamy Thangaraju
1Department of Biochemistry and Molecular Biology, Medical College of Georgia, Georgia Health Sciences University, Augusta, GA 30912, U.S.A.
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Vadivel Ganapathy
Vadivel Ganapathy
1
1Department of Biochemistry and Molecular Biology, Medical College of Georgia, Georgia Health Sciences University, Augusta, GA 30912, U.S.A.
1To whom correspondence should be addressed (email vganapat@georgiahealth.edu).
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Publisher: Portland Press Ltd
Received:
August 06 2012
Revision Received:
October 29 2012
Accepted:
November 20 2012
Accepted Manuscript online:
November 20 2012
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2013 Biochemical Society
2013
Biochem J (2013) 450 (1): 169–178.
Article history
Received:
August 06 2012
Revision Received:
October 29 2012
Accepted:
November 20 2012
Accepted Manuscript online:
November 20 2012
Citation
Veena Coothankandaswamy, Selvakumar Elangovan, Nagendra Singh, Puttur D. Prasad, Muthusamy Thangaraju, Vadivel Ganapathy; The plasma membrane transporter SLC5A8 suppresses tumour progression through depletion of survivin without involving its transport function. Biochem J 15 February 2013; 450 (1): 169–178. doi: https://doi.org/10.1042/BJ20121248
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