MUC13 contributes to rewiring of glucose metabolism in pancreatic cancer.
MUC13 contributes to rewiring of glucose metabolism in pancreatic cancer.
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DOI：
10.1038/s41389-018-0031-0
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发表时间：
2018-02-22
期刊：
影响因子：
6.2
通讯作者：
Jaggi M
中科院分区：
文献类型：
--
作者：
Kumari S;Khan S;Gupta SC;Kashyap VK;Yallapu MM;Chauhan SC;Jaggi M
胰腺肿瘤因高葡萄糖代谢而改变，通常预后极差。最近，我们已经表明，MUC 13，这是高度表达的胰腺肿瘤，促进肿瘤进展，通过调节HER 2受体酪氨酸激酶活性。在此，我们研究了一种新的，MUC 13介导的分子机制，负责更高的葡萄糖代谢在胰腺肿瘤。我们的研究结果表明，MUC 13的表达导致NF-κB p65的活化/核转位和IκB的磷酸化，这反过来又上调参与葡萄糖代谢的重要蛋白（Glut-1，c-Myc和Bcl-2）的表达。MUC 13在功能上与Glut-1相互作用并稳定Glut-1，以引发胰腺癌细胞中负责更高葡萄糖摄取的下游事件。通过过表达和敲低技术改变MUC 13表达有效地调节胰腺癌细胞中的葡萄糖摄取、乳酸分泌和转移表型。NF-κB抑制剂柳氮磺胺吡啶消除MUC 13和Glut-1相互作用，并减弱与MUC 13诱导的葡萄糖代谢相关的事件。胰腺导管腺癌（PDAC）患者组织样品也显示这两种蛋白质的表达之间的正相关性。这些结果描述了MUC 13如何重新连接异常的葡萄糖代谢以增强胰腺癌的侵袭性，并揭示了为这种异常困难的癌症开发新的治疗策略的新机制。
Pancreatic tumors are rewired for high-glucose metabolism and typically present with exceptionally poor prognosis. Recently, we have shown that MUC13, which is highly expressed in pancreatic tumors, promotes tumor progression via modulation of HER2 receptor tyrosine kinase activity. Herein, we investigate a novel, MUC13-mediated molecular mechanism responsible for higher glucose metabolism in pancreatic tumors. Our results demonstrate that MUC13 expression leads to the activation/nuclear translocation of NF-κB p65 and phosphorylation of IκB, which in turn upregulates the expression of important proteins (Glut-1, c-Myc, and Bcl-2) that are involved in glucose metabolism. MUC13 functionally interacts and stabilizes Glut-1 to instigate downstream events responsible for higher glucose uptake in pancreatic cancer cells. Altered MUC13 expression by overexpression and knockdown techniques effectively modulated glucose uptake, lactate secretion, and metastatic phenotypes in pancreatic cancer cells. NF-κB inhibitor, Sulfasalazine, abrogates the MUC13 and Glut-1 interaction, and attenuates events associated with MUC13-induced glucose metabolism. Pancreatic ductal adenocarcinoma (PDAC) patient tissue samples also show a positive correlation between the expression of these two proteins. These results delineate how MUC13 rewire aberrant glucose metabolism to enhance aggressiveness of pancreatic cancer and revealed a novel mechanism to develop newer therapeutic strategies for this exceptionally difficult cancer.
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影响因子：
5.7
作者：
Chauhan SC;Ebeling MC;Maher DM;Koch MD;Watanabe A;Aburatani H;Lio Y;Jaggi M
通讯作者：
Jaggi M
肿瘤微环境产生的酸度驱动局部侵袭。
影响因子：
11.2
作者：
Estrella V;Chen T;Lloyd M;Wojtkowiak J;Cornnell HH;Ibrahim-Hashim A;Bailey K;Balagurunathan Y;Rothberg JM;Sloane BF;Johnson J;Gatenby RA;Gillies RJ
通讯作者：
Gillies RJ
DOI：
10.1097/gim.0b013e31818b0d9b
发表时间：
2008-11
期刊：
Genetics in medicine : official journal of the American College of Medical Genetics
影响因子：
--
作者：
DeBerardinis RJ
通讯作者：
DeBerardinis RJ
DOI：
10.1038/nrgastro.2013.120
发表时间：
2013-10
期刊：
Nature reviews. Gastroenterology & hepatology
影响因子：
--
作者：
通讯作者：
--
影响因子：
64.5
作者：
Ying H;Kimmelman AC;Lyssiotis CA;Hua S;Chu GC;Fletcher-Sananikone E;Locasale JW;Son J;Zhang H;Coloff JL;Yan H;Wang W;Chen S;Viale A;Zheng H;Paik JH;Lim C;Guimaraes AR;Martin ES;Chang J;Hezel AF;Perry SR;Hu J;Gan B;Xiao Y;Asara JM;Weissleder R;Wang YA;Chin L;Cantley LC;DePinho RA
通讯作者：
DePinho RA