Alterations of monocarboxylate transporter densities during hypoxia in brain and breast tumour cells
Alterations of monocarboxylate transporter densities during hypoxia in brain and breast tumour cells
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DOI：
10.1007/s13402-012-0081-9
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发表时间：
2012-06-01
影响因子：
6.6
通讯作者：
Bergersen, Linda H.
中科院分区：
文献类型：
--
作者：
Cheng, Chang;Edin, Nina F. Jeppesen;Bergersen, Linda H.
背景肿瘤细胞的特征是有氧糖酵解，它为肿瘤的增殖提供生物量，并通过单羧酸转运体(MCTs)将乳酸排出细胞外，从而导致细胞外酸化。缺乏和容易痉挛的肿瘤血管会导致不同程度的缺氧，这有利于肿瘤细胞的存活和转移。脑转移常发生在晚期乳腺癌患者中。因此需要有效的治疗策略来对抗乳腺癌脑转移。材料与方法为了确定乳酸交换能力的差异，在4%和20%氧气条件下培养人T-47D乳腺癌细胞和人胶质母细胞瘤T98G细胞，并用免疫金标记法定量检测细胞质膜上MCT1、MCT2和MCT4的表达。结果在常氧条件下，两种肿瘤细胞均高表达低亲和力转运蛋白MCT4，而对于高亲和力转运蛋白，乳腺肿瘤细胞优先表达MCT1，而脑肿瘤细胞表达MCT2而不是MCT1。MCT1和MCT4在低氧条件下在乳腺和脑肿瘤细胞中的表达均上调。MCT2在缺氧性乳腺癌细胞中的表达也增加，但在缺氧性脑肿瘤细胞中的表达减少。定量免疫印迹显示低氧诱导的蛋白质水平变化相似。结论MCTs在不同类型的缺氧性和常氧性肿瘤细胞表膜上的差异表达和调控，为通过MCTs的选择性靶向治疗肿瘤提供了基础。选择性地抑制多种MCT可能是一种有效的方法来熄灭原发乳腺肿瘤和脑转移癌组织中的重要能量来源。
Background Tumour cells are characterized by aerobic glycolysis, which provides biomass for tumour proliferation and leads to extracellular acidification through efflux of lactate via monocarboxylate transporters (MCTs). Deficient and spasm-prone tumour vasculature causes variable hypoxia, which favours tumour cell survival and metastases. Brain metastases frequently occur in patients with advanced breast cancer. Effective treatment strategies are therefore needed against brain metastasis from breast carcinoma.Material and methods In order to identify differences in the capacity for lactate exchange, human T-47D breast cancer cells and human glioblastoma T98G cells were grown under 4 % or 20 % oxygen conditions and examined for MCT1, MCT2 and MCT4 expression on plasma membranes by quantitative post embedding immunogold electron microscopy. Whereas previous studies on MCT expression in tumours have recorded mRNA and protein levels in cell extracts, we examined concentrations of the proteins in the microvillous plasma membrane protrusions specialized for transmembrane transport.Results In normoxia, both tumour cell types highly expressed the low affinity transporter MCT4, which is thought to mainly mediate monocarboxylate efflux, while for high affinity transport the breast tumour cells preferentially expressed MCT1 and the brain tumour cells resembled brain neurons in expressing MCT2, rather than MCT1. The expressions of MCT1 and MCT4 were upregulated in hypoxic conditions in both breast and brain tumour cells. The expression of MCT2 also increased in hypoxic breast cancer cells, but decreased in hypoxic brain tumour cells. Quantitative immunoblots showed similar hypoxia induced changes in the protein levels.Conclusion The differential expression and regulation of MCTs in the surface membranes of hypoxic and normoxic tumour cells of different types provide a foundation for innovation in tumour therapy through the selective targeting of MCTs. Selective inhibition of various MCTs could be an efficient way to quench an important energy source in both original breast tumour and metastatic cancer tissue in the brain.