Monocarboxylate transport inhibition potentiates the cytotoxic effect of 5-fluorouracil in colorectal cancer cells
Monocarboxylate transport inhibition potentiates the cytotoxic effect of 5-fluorouracil in colorectal cancer cells
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DOI：
10.1016/j.canlet.2015.05.015
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发表时间：
2015-08-28
期刊：
影响因子：
9.7
通讯作者：
Baltazar, Fatima
中科院分区：
文献类型：
--
作者：
Amorim, Ricardo;Pinheiro, Celine;Baltazar, Fatima
癌细胞主要依靠糖酵解来满足其能量需求，产生大量乳酸，这些乳酸被单羧酸转运体（mct）挤压到肿瘤微环境中。mct在结直肠癌（CRC）细胞存活中的作用尚不清楚。在这项研究中，我们旨在更好地理解这一问题，并利用这些转运蛋白作为新的治疗靶点单独或联合CRC经典化疗药物5-氟尿嘧啶。为此，我们表征了MCT活性抑制在正常和CRC衍生细胞系中的作用，并评估了MCT与5-FU联合抑制的效果。在这里，我们证明了使用CHC （α -氰基-4-羟基肉桂酸），DIDS（4,4'-二异硫氰基二苯乙烯-2,2'-二磺酸）和槲皮素抑制MCT可降低CRC细胞的活力，破坏糖酵解表型，抑制增殖并增强细胞死亡。这些结果通过RNA干扰对MCT1/4的特异性抑制得到证实。值得注意的是，我们发现5-FU的细胞毒性通过抑制CRC细胞中的乳酸转运而增强，无论是通过活性抑制还是表达沉默。这些发现为mct在CRC维持和生存中的关键作用提供了新的证据，也为将这些转运体作为CRC常规治疗联合使用的潜在新治疗靶点提供了新的证据。2015爱思唯尔爱尔兰有限公司版权所有。
Cancer cells rely mostly on glycolysis to meet their energetic demands, producing large amounts of lactate that are extruded to the tumour microenvironment by monocarboxylate transporters (MCTs). The role of MCTs in the survival of colorectal cancer (CRC) cells is scarce and poorly understood. In this study, we aimed to better understand this issue and exploit these transporters as novel therapeutic targets alone or in combination with the CRC classical chemotherapeutic drug 5-Fluorouracil.For that purpose, we characterized the effects of MCT activity inhibition in normal and CRC derived cell lines and assessed the effect of MCT inhibition in combination with 5-FU.Here, we demonstrated that MCT inhibition using CHC (alpha-cyano-4-hydroxycinnamic acid), DIDS (4,4'-diisothiocyanatostilbene-2,2'-disulphonic acid) and quercetin decreased cell viability, disrupted the glycolytic phenotype, inhibited proliferation and enhanced cell death in CRC cells. These results were confirmed by specific inhibition of MCT1/4 by RNA interference. Notably, we showed that 5-FU cytotoxicity was potentiated by lactate transport inhibition in CRC cells, either by activity inhibition or expression silencing.These findings provide novel evidence for the pivotal role of MCTs in CRC maintenance and survival, as well as for the use of these transporters as potential new therapeutic targets in combination with CRC conventional therapy. (C) 2015 Elsevier Ireland Ltd. All rights reserved.