MUC16-mediated activation of mTOR and c-MYC reprograms pancreatic cancer metabolism
MUC16-mediated activation of mTOR and c-MYC reprograms pancreatic cancer metabolism
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DOI：
10.18632/oncotarget.4078
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发表时间：
2015-08-07
期刊：
影响因子：
--
通讯作者：
Singh, Pankaj K.
中科院分区：
文献类型：
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作者：
Shukla, Surendra K.;Gunda, Venugopal;Singh, Pankaj K.
MUC 16是一种跨膜粘蛋白，可促进胰腺癌的进展和转移。在目前的研究中，我们观察到MUC 16敲低胰腺癌细胞表现出葡萄糖摄取和乳酸分泌减少沿着迁移和侵袭潜力降低，这可以通过向培养基中补充乳酸（有氧糖酵解的终产物）来恢复。MUC 16敲低导致mTOR活性的抑制和其下游靶标c-MYC（细胞生长、增殖和代谢中的关键参与者）的表达减少。MUC 16敲除胰腺癌细胞中c-MYC的异位表达恢复了改变的细胞生理学。我们基于LC-MS/MS的代谢组学研究表明，与对照相比，MUC 16敲低胰腺癌细胞中的总体代谢改变。具体而言，糖酵解和核苷酸代谢物池显著减少。我们在人胰腺癌患者的原发性肿瘤组织标本中观察到与MUC 16表达相关的类似代谢改变。总之，我们的研究结果表明，MUC 16通过增加糖酵解和增强运动性和侵袭性在胰腺癌细胞的代谢重编程中起重要作用。
MUC16, a transmembrane mucin, facilitates pancreatic adenocarcinoma progression and metastasis. In the current studies, we observed that MUC16 knockdown pancreatic cancer cells exhibit reduced glucose uptake and lactate secretion along with reduced migration and invasion potential, which can be restored by supplementing the culture media with lactate, an end product of aerobic glycolysis. MUC16 knockdown leads to inhibition of mTOR activity and reduced expression of its downstream target c-MYC, a key player in cellular growth, proliferation and metabolism. Ectopic expression of c-MYC in MUC16 knockdown pancreatic cancer cells restores the altered cellular physiology. Our LC-MS/MS based metabolomics studies indicate global metabolic alterations in MUC16 knockdown pancreatic cancer cells, as compared to the controls. Specifically, glycolytic and nucleotide metabolite pools were significantly decreased. We observed similar metabolic alterations that correlated with MUC16 expression in primary tumor tissue specimens from human pancreatic adenocarcinoma cancer patients. Overall, our results demonstrate that MUC16 plays an important role in metabolic reprogramming of pancreatic cancer cells by increasing glycolysis and enhancing motility and invasiveness.