Glutaminolysis drives membrane trafficking to promote invasiveness of breast cancer cells.
Glutaminolysis drives membrane trafficking to promote invasiveness of breast cancer cells.
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DOI：
10.1038/s41467-017-02101-2
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发表时间：
2017-12-21
影响因子：
16.6
通讯作者：
Norman JC
中科院分区：
文献类型：
--
作者：
Dornier E;Rabas N;Mitchell L;Novo D;Dhayade S;Marco S;Mackay G;Sumpton D;Pallares M;Nixon C;Blyth K;Macpherson IR;Rainero E;Norman JC
谷氨酰胺分解作用在提供代谢产物以支持肿瘤生长方面的作用已被证实，但谷氨酰胺代谢在侵袭过程中的参与尚不清楚。我们在这里展示了正常的乳腺上皮细胞消耗谷氨酰胺，但不分泌谷氨酸。的确，细胞外低水平的谷氨酸是维持上皮细胞动态平衡所必需的，谷氨酸的供应推动了上皮形态的破坏，并促进了侵袭性表型的关键特征，如管腔填充和基底膜破坏。相比之下，浸润性乳腺癌细胞的原代培养将谷氨酰胺转化为谷氨酸，谷氨酸通过XC逆向转运蛋白系统从细胞中释放出来，激活代谢性谷氨酸受体。这有助于这些细胞的内在侵袭性，通过上调依赖Rab27的跨膜基质金属蛋白酶MT1-MMP的循环，促进导致基底膜破坏的侵袭行为。这些数据表明，获得释放谷氨酸的能力是疾病侵袭性的关键分水岭。众所周知，谷氨酰胺代谢支持肿瘤生长。在这里，作者表明，癌细胞还利用谷氨酰胺通过将其转化为谷氨酸来促进侵袭力，谷氨酸在分泌时激活代谢性谷氨酸受体，刺激基质金属蛋白酶循环到细胞表面。
The role of glutaminolysis in providing metabolites to support tumour growth is well-established, but the involvement of glutamine metabolism in invasive processes is yet to be elucidated. Here we show that normal mammary epithelial cells consume glutamine, but do not secrete glutamate. Indeed, low levels of extracellular glutamate are necessary to maintain epithelial homoeostasis, and provision of glutamate drives disruption of epithelial morphology and promotes key characteristics of the invasive phenotype such as lumen-filling and basement membrane disruption. By contrast, primary cultures of invasive breast cancer cells convert glutamine to glutamate which is released from the cell through the system Xc- antiporter to activate a metabotropic glutamate receptor. This contributes to the intrinsic aggressiveness of these cells by upregulating Rab27-dependent recycling of the transmembrane matrix metalloprotease, MT1-MMP to promote invasive behaviour leading to basement membrane disruption. These data indicate that acquisition of the ability to release glutamate is a key watershed in disease aggressiveness. Glutamine metabolism is well known to support tumour growth. Here the authors show that cancer cells also utilize glutamine to promote invasiveness by converting it to glutamate, which upon secretion activates metabotropic glutamate receptors to stimulate matrix metalloproteases recycling to the cell surface.
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DOI：
10.1146/annurev.pharmtox.011008.145533
发表时间：
2010
影响因子：
12.5
作者：
Niswender CM;Conn PJ
通讯作者：
Conn PJ
影响因子：
12.3
作者：
Herschkowitz JI;Simin K;Weigman VJ;Mikaelian I;Usary J;Hu Z;Rasmussen KE;Jones LP;Assefnia S;Chandrasekharan S;Backlund MG;Yin Y;Khramtsov AI;Bastein R;Quackenbush J;Glazer RI;Brown PH;Green JE;Kopelovich L;Furth PA;Palazzo JP;Olopade OI;Bernard PS;Churchill GA;Van Dyke T;Perou CM
通讯作者：
Perou CM
影响因子：
4
作者：
De Franceschi N;Hamidi H;Alanko J;Sahgal P;Ivaska J
通讯作者：
Ivaska J
影响因子：
56.9
作者：
Cukierman, E;Pankov, R;Yamada, KM
通讯作者：
Yamada, KM
影响因子：
4.8
作者：
Debnath, J;Muthuswamy, SK;Brugge, JS
通讯作者：
Brugge, JS