Paroder Viktoriya, Spencer Shelly R, Paroder Monika, Arango Diego, Schwartz Simo, Mariadason John M, Augenlicht Leonard H, Eskandari Sepehr, Carrasco Nancy
Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Proc Natl Acad Sci U S A. 2006 May 9;103(19):7270-5. doi: 10.1073/pnas.0602365103. Epub 2006 May 2.
We report an extensive characterization of the Na(+)/monocarboxylate transporter (SMCT), a plasma membrane protein that mediates active transport of monocarboxylates such as propionate and nicotinate, and we show that SMCT may play a role in colorectal cancer diagnosis. SMCT, the product of the SLC5A8 gene, is 70% similar to the Na(+)/I(-) symporter, the protein that mediates active I(-) uptake in the basolateral surface of thyrocytes and other cells. SMCT was reported in the apical surface of thyrocytes and formerly proposed also to transport I(-) and was called the apical I(-) transporter. However, it is now clear that SMCT does not transport I(-). Here we demonstrate a high-affinity Na(+)-dependent monocarboxylate transport system in thyroid cells, which is likely to be SMCT. We show that, whereas thyroidal Na(+)/I(-) symporter expression is thyroid-stimulating hormone (TSH)-dependent and basolateral, SMCT expression is TSH-independent and apical not only in the thyroid but also in kidney and colon epithelial cells and in polarized Madin-Darby canine kidney cells. We determine the kinetic parameters of SMCT activity and show its inhibition by ibuprofen (K(i) = 73 +/- 9 microM) in Xenopus laevis oocytes. SMCT was proposed to be a tumor suppressor in colon cancer. Significantly, we show that higher expression of SMCT in colon samples from 113 colorectal cancer patients correlates with longer disease-free survival, suggesting that SMCT expression may be a favorable indicator of colorectal cancer prognosis.
我们报告了对钠/单羧酸转运体（SMCT）的广泛表征，它是一种质膜蛋白，介导丙酸盐和烟酸盐等单羧酸的主动转运，并且我们表明SMCT可能在结直肠癌诊断中发挥作用。SMCT是SLC5A8基因的产物，与钠/碘同向转运体有70%的相似性，钠/碘同向转运体是介导甲状腺细胞和其他细胞基底外侧表面碘主动摄取的蛋白质。SMCT曾在甲状腺细胞的顶端表面被报道，之前也有人提出它也转运碘，并被称为顶端碘转运体。然而，现在很清楚SMCT并不转运碘。在这里我们证明了甲状腺细胞中存在一种高亲和力的钠依赖性单羧酸转运系统，它很可能就是SMCT。我们表明，甲状腺钠/碘同向转运体的表达依赖于促甲状腺激素（TSH）且位于基底外侧，而SMCT的表达不仅在甲状腺中，而且在肾和结肠上皮细胞以及极化的Madin-Darby犬肾细胞中都是不依赖于TSH且位于顶端。我们确定了SMCT活性的动力学参数，并在非洲爪蟾卵母细胞中显示了布洛芬对其的抑制作用（抑制常数K(i)=73±9微摩尔）。有人提出SMCT是结肠癌的一种肿瘤抑制因子。重要的是，我们表明113例结直肠癌患者结肠样本中SMCT的高表达与更长的无病生存期相关，这表明SMCT的表达可能是结直肠癌预后的一个有利指标。
