Kumari Sonam, Khan Sheema, Gupta Subash C, Kashyap Vivek K, Yallapu Murali M, Chauhan Subhash C, Jaggi Meena
Department of Pharmaceutical Sciences and Center for Cancer Research, University of Tennessee Health Science Center, Memphis, TN, USA.
Department of Biochemistry, Institute of Science, Banaras Hindu University, Varanasi, India.
Oncogenesis. 2018 Feb 22;7(2):19. doi: 10.1038/s41389-018-0031-0.
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.
胰腺肿瘤因高糖代谢而发生重编程，通常预后极差。最近，我们发现胰腺肿瘤中高表达的MUC13通过调节HER2受体酪氨酸激酶活性促进肿瘤进展。在此，我们研究一种由MUC13介导的、导致胰腺肿瘤中更高糖代谢的新分子机制。我们的结果表明，MUC13的表达导致NF-κB p65的激活/核转位以及IκB的磷酸化，进而上调参与糖代谢的重要蛋白质（Glut-1、c-Myc和Bcl-2）的表达。MUC13在功能上与Glut-1相互作用并使其稳定，从而引发胰腺癌细胞中更高葡萄糖摄取的下游事件。通过过表达和敲低技术改变MUC13的表达可有效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可消除MUC13与Glut-1的相互作用，并减弱与MUC13诱导的糖代谢相关的事件。胰腺导管腺癌（PDAC）患者组织样本也显示这两种蛋白的表达呈正相关。这些结果阐明了MUC13如何重塑异常糖代谢以增强胰腺癌的侵袭性，并揭示了一种为这种极难治疗的癌症开发新治疗策略的新机制。
