Abstract 1310: SLC5A8 functions as a tumor suppressor through redistribution and depletion of survivin

Abstract

Abstract SLC5A8 is a Na+-coupled transporter for lactate, pyruvate, and nicotinate. Its expression is silenced in a wide variety of cancers including breast, colon, brain, thyroid, prostate, and pancreas, by methylation of CpG islands of its promoter. Increasing SLC5A8 expression through inhibition of DNA methylation in cancer cells leads to apoptosis. The silencing of SLC5A8 is essential for tumor cell survival because of the ability of this transporter to increase cellular levels of pyruvate by actively transporting circulating pyruvate into cells. Pyruvate is considered as an efficient fuel source for tumor cells, but our studies have shown that this metabolite is actually a tumor suppressor through its ability to inhibit HDAC1 and HDAC3. Our recent studies have shown that HDAC inhibition alone is not responsible for the tumor suppressive function of SLC5A8. Survivin, an anti-apoptotic protein and also a chromosomal passenger complex protein, is sequestered to the plasma membrane by SLC5A8 through protein-protein interaction and is also downregulated by transcriptional inhibition. This phenomenon is seen in two different human breast cancer cell lines, MCF7 and MB231. These cell lines do not express SLC5A8, and survivin is localized predominantly in the nucleus in these cells. However, upon lentiviral-mediated expression of SLC5A8 in these cells, survivin gets depleted in the nucleus but gets concentrated in the plasma membrane, colocalizing with the transporter. In the absence of SLC5A8, survivin localizes at the centromere during metaphase, and is essential for recruitment of the other component of the chromosomal passenger complex, Aurora B, to the centromere. But SLC5A8-induced translocation of survivin out of the nucleus disrupts the chromosomal passenger complex and consequently interferes with cell division. Additionally, apoptosis is induced in these cells upon forced expression of the transporter. Redistribution of survivin from the nucleus to the plasma membrane is not the only change observed in breast cancer cells upon SLC5A8 expression. The total cellular pool of survivin is also decreased, resulting from decreased transcription of the survivin gene. This process is associated with decreased phosphorylation of STAT3. The redistribution and depletion of survivin in these breast cancer cells upon SLC5A8 expression increases their sensitivity to chemotherapeutic agents. All these effects are independent of HDAC inhibition because these effects are seen in the absence of pyruvate in the culture medium. The growth of MB231 cells in mouse xenografts is drastically reduced when SLC5A8 is expressed. We conclude that SLC5A8 functions as a tumor suppressor by two different mechanisms, one involving HDAC inhibition in the presence of pyruvate and the other involving survivin redistribution and depletion. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1310. doi:1538-7445.AM2012-1310