title: The plasma membrane transporter SLC5A8 suppresses tumour progression through depletion of survivin without involving its transport function.
abstract: 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.
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical College of Georgia, Georgia Health Sciences University, Augusta, GA 30912, USA.
authors.forename: Veena
authors.initials: V
authors.lastname: Coothankandaswamy
authors.forename: Selvakumar
authors.initials: S
authors.lastname: Elangovan
authors.forename: Nagendra
authors.initials: N
authors.lastname: Singh
authors.forename: Puttur D
authors.initials: PD
authors.lastname: Prasad
authors.forename: Muthusamy
authors.initials: M
authors.lastname: Thangaraju
authors.forename: Vadivel
authors.initials: V
authors.lastname: Ganapathy
mesh_terms: D000818:Animals; D017209:Apoptosis; D001692:Biological Transport; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D027682:Cation Transport Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism*; D005260:Female; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D027501:Monocarboxylic Acid Transporters; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D000077022:Survivin; D014183:Transplantation, Heterologous
chemical_list: C107489:BIRC5 protein, human; D027682:Cation Transport Proteins; D051034:Inhibitor of Apoptosis Proteins; D027501:Monocarboxylic Acid Transporters; C476760:SLC5A8 protein, human; D000077022:Survivin