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MCT1 介导的有毒分子转运是靶向糖酵解肿瘤的有效策略。

MCT1-mediated transport of a toxic molecule is an effective strategy for targeting glycolytic tumors.

机构信息

Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, USA.

出版信息

Nat Genet. 2013 Jan;45(1):104-8. doi: 10.1038/ng.2471. Epub 2012 Dec 2.

DOI:10.1038/ng.2471
PMID:23202129
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3530647/
Abstract

There is increasing evidence that oncogenic transformation modifies the metabolic program of cells. A common alteration is the upregulation of glycolysis, and efforts to target glycolytic enzymes for anticancer therapy are under way. Here, we performed a genome-wide haploid genetic screen to identify resistance mechanisms to 3-bromopyruvate (3-BrPA), a drug candidate that inhibits glycolysis in a poorly understood fashion. We identified the SLC16A1 gene product, MCT1, as the main determinant of 3-BrPA sensitivity. MCT1 is necessary and sufficient for 3-BrPA uptake by cancer cells. Additionally, SLC16A1 mRNA levels are the best predictor of 3-BrPA sensitivity and are most elevated in glycolytic cancer cells. Furthermore, forced MCT1 expression in 3-BrPA-resistant cancer cells sensitizes tumor xenografts to 3-BrPA treatment in vivo. Our results identify a potential biomarker for 3-BrPA sensitivity and provide proof of concept that the selectivity of cancer-expressed transporters can be exploited for delivering toxic molecules to tumors.

摘要

越来越多的证据表明，致癌转化改变了细胞的代谢程序。常见的改变是糖酵解的上调，并且正在努力针对糖酵解酶进行抗癌治疗。在这里，我们进行了全基因组单倍体遗传筛选，以鉴定对 3-溴丙酮酸（3-BrPA）的抗性机制，3-BrPA 是一种以未被充分了解的方式抑制糖酵解的候选药物。我们确定 SLC16A1 基因产物 MCT1 是 3-BrPA 敏感性的主要决定因素。MCT1 是癌细胞摄取 3-BrPA 的必需和充分条件。此外，SLC16A1 mRNA 水平是 3-BrPA 敏感性的最佳预测因子，在糖酵解癌细胞中升高最为明显。此外，在 3-BrPA 耐药癌细胞中强制表达 MCT1 可使肿瘤异种移植物对 3-BrPA 治疗敏感。我们的结果确定了 3-BrPA 敏感性的潜在生物标志物，并提供了概念验证，即可以利用癌细胞表达的转运蛋白的选择性将有毒分子递送到肿瘤中。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3729/3530647/0d50b0737cfa/nihms417628f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3729/3530647/dc12b3e00e48/nihms417628f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3729/3530647/2393422abdd3/nihms417628f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3729/3530647/907d7b1850be/nihms417628f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3729/3530647/0d50b0737cfa/nihms417628f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3729/3530647/dc12b3e00e48/nihms417628f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3729/3530647/2393422abdd3/nihms417628f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3729/3530647/907d7b1850be/nihms417628f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3729/3530647/0d50b0737cfa/nihms417628f4.jpg

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