Inhibition of FASN and ERα signalling during hyperglycaemia-induced matrix-specific EMT promotes breast cancer cell invasion via a caveolin-1-dependent mechanism.
Inhibition of FASN and ERα signalling during hyperglycaemia-induced matrix-specific EMT promotes breast cancer cell invasion via a caveolin-1-dependent mechanism.
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DOI：
10.1016/j.canlet.2018.01.028
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发表时间：
2018-04-10
期刊：
影响因子：
9.7
通讯作者：
Perks CM
中科院分区：
文献类型：
--
作者：
Zielinska HA;Holly JMP;Bahl A;Perks CM
由于紊乱的代谢状况，如肥胖和糖尿病可能是乳腺癌进展和治疗失败的关键决定因素，我们的目的是确定其促癌作用的机制。使用非侵入性的上皮样ERα阳性MCF-7和T47 D人乳腺癌细胞，我们发现高脂血症诱导上皮向间质转化（EMT），这是导致转移性疾病发展的关键程序。这通过上皮标志物E-钙粘蛋白的丢失以及间充质标志物如波形蛋白、纤连蛋白和转录因子SLUG的增加以及细胞生长和侵袭的增强来证明。这些表型变化仅在纤维连接蛋白上生长的细胞中观察到，而在胶原蛋白上接种的细胞中未观察到。分析代谢参数，我们发现高血压诱导的基质特异性EMT通过上调葡萄糖摄取、乳酸释放和特异性糖酵解酶和转运蛋白来促进瓦尔堡效应。我们发现，脂肪酸合成酶（FXR）和下游ERα的沉默，我们以前在这些细胞中介导高血压诱导的化疗耐药性，导致细胞生长抑制：然而，这也导致细胞侵袭和SLUG mRNA水平通过一种新的小窝蛋白-1依赖性机制显着增强。高脂血症和纤维连接蛋白诱导ERα阳性乳腺癌细胞EMT，并促进瓦尔堡效应。FXR/ERα信号通路的抑制导致细胞侵袭的显著增强。Caveolin-1介导由靶向FXR或ERα触发的促侵袭表型。
Since disturbed metabolic conditions such as obesity and diabetes can be critical determinants of breast cancer progression and therapeutic failure, we aimed to determine the mechanism responsible for their pro-oncogenic effects. Using non-invasive, epithelial-like ERα-positive MCF-7 and T47D human breast cancer cells we found that hyperglycaemia induced epithelial to mesenchymal transition (EMT), a key programme responsible for the development of metastatic disease. This was demonstrated by loss of the epithelial marker E-cadherin together with increases in mesenchymal markers such as vimentin, fibronectin and the transcription factor SLUG, together with an enhancement of cell growth and invasion. These phenotypic changes were only observed with cells grown on fibronectin and not with those plated on collagen. Analyzing metabolic parameters, we found that hyperglycaemia-induced, matrix-specific EMT promoted the Warburg effect by upregulating glucose uptake, lactate release and specific glycolytic enzymes and transporters. We showed that silencing of fatty acid synthase (FASN) and the downstream ERα, which we showed previously to mediate hyperglycaemia-induced chemoresistance in these cells, resulted in suppression of cell growth: however, this also resulted in a dramatic enhancement of cell invasion and SLUG mRNA levels via a novel caveolin-1-dependent mechanism. Exposure to hyperglycaemia and fibronectin induced EMT and promoted the Warburg effect in ERα-positive breast cancer cells. Inhibition of the FASN/ERα signalling pathway resulted in a dramatic enhancement of cell invasion. Caveolin-1 mediated the pro-invasive phenotype triggered by targeting FASN or the ERα.
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影响因子：
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作者：
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