Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, Via Vetoio, Coppito 2, 67100 L'Aquila, Italy.
BMC Cancer. 2014 Mar 5;14:154. doi: 10.1186/1471-2407-14-154.
Cancer cell adopts peculiar metabolic strategies aimed to sustain the continuous proliferation in an environment characterized by relevant fluctuations in oxygen and nutrient levels. Monocarboxylate transporters MCT1 and MCT4 can drive such adaptation permitting the transport across plasma membrane of different monocarboxylic acids involved in energy metabolism.
Role of MCTs in tumor-stroma metabolic relationship was investigated in vitro and in vivo using transformed prostate epithelial cells, carcinoma cell lines and normal fibroblasts. Moreover prostate tissues from carcinoma and benign hypertrophy cases were analyzed for individuating clinical-pathological implications of MCT1 and MCT4 expression.
Transformed prostate epithelial (TPE) and prostate cancer (PCa) cells express both MCT1 and MCT4 and demonstrated variable dependence on aerobic glycolysis for maintaining their proliferative rate. In glucose-restriction the presence of L-lactate determined, after 24 h of treatment, in PCa cells the up-regulation of MCT1 and of cytochrome c oxidase subunit I (COX1), and reduced the activation of AMP-activated protein kinase respect to untreated cells. The blockade of MCT1 function, performed by si RNA silencing, determined an appreciable antiproliferative effect when L-lactate was utilized as energetic fuel. Accordingly L-lactate released by high glycolytic human diploid fibroblasts WI-38 sustained survival and growth of TPE and PCa cells in low glucose culture medium. In parallel, the treatment with conditioned medium from PCa cells was sufficient to induce glycolytic metabolism in WI-38 cells, with upregulation of HIF-1a and MCT4. Co-injection of PCa cells with high glycolytic WI-38 fibroblasts determined an impressive increase in tumor growth rate in a xenograft model that was abrogated by MCT1 silencing in PCa cells. The possible interplay based on L-lactate shuttle between tumor and stroma was confirmed also in human PCa tissue where we observed a positive correlation between stromal MCT4 and tumor MCT1 expression.
Our data demonstrated that PCa progression may benefit of MCT1 expression in tumor cells and of MCT4 in tumor-associated stromal cells. Therefore, MCTs may result promising therapeutic targets in different phases of neoplastic transformation according to a strategy aimed to contrast the energy metabolic adaptation of PCa cells to stressful environments.
癌细胞采用独特的代谢策略，以维持在氧气和营养水平波动较大的环境中的持续增殖。单羧酸转运蛋白 MCT1 和 MCT4 可促进这种适应，允许不同的参与能量代谢的单羧酸穿过质膜运输。
使用转化的前列腺上皮细胞、癌细胞系和正常成纤维细胞在体外和体内研究了 MCTs 在肿瘤-基质代谢关系中的作用。此外，还分析了来自癌和良性肥大病例的前列腺组织，以确定 MCT1 和 MCT4 表达的临床病理意义。
转化的前列腺上皮（TPE）和前列腺癌细胞均表达 MCT1 和 MCT4，并表现出对有氧糖酵解维持增殖率的不同依赖。在葡萄糖限制下，24 小时治疗后，L-乳酸在前列腺癌细胞中上调 MCT1 和细胞色素 c 氧化酶亚基 I（COX1），并降低 AMP 激活蛋白激酶相对于未处理细胞的激活。通过 siRNA 沉默阻断 MCT1 功能，当 L-乳酸被用作能量燃料时，可显著抑制增殖。因此，高糖酵解的人二倍体成纤维细胞 WI-38 释放的 L-乳酸可维持 TPE 和前列腺癌细胞在低糖培养物中的存活和生长。平行地，用来自前列腺癌细胞的条件培养基处理足以诱导 WI-38 细胞中的糖酵解代谢，上调 HIF-1a 和 MCT4。在异种移植模型中，将高糖酵解的 WI-38 成纤维细胞与前列腺癌细胞共注射可显著增加肿瘤生长速度，而在前列腺癌细胞中沉默 MCT1 可消除这种作用。在人前列腺癌组织中也证实了基于肿瘤和基质之间的 L-乳酸穿梭的可能相互作用，我们观察到基质 MCT4 与肿瘤 MCT1 表达之间存在正相关。
我们的数据表明，前列腺癌的进展可能受益于肿瘤细胞中 MCT1 的表达和肿瘤相关基质细胞中 MCT4 的表达。因此，MCT 可能成为不同肿瘤转化阶段有前途的治疗靶点，根据一种旨在对抗前列腺癌细胞对应激环境的能量代谢适应的策略。
