Strengthened glycolysis under hypoxia supports tumor symbiosis and hexosamine biosynthesis in pancreatic adenocarcinoma
Strengthened glycolysis under hypoxia supports tumor symbiosis and hexosamine biosynthesis in pancreatic adenocarcinoma
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DOI：
10.1073/pnas.1219555110
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发表时间：
2013-03-05
影响因子：
11.1
通讯作者：
Vasseur, Sophie
中科院分区：
文献类型：
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作者：
Guillaumond, Fabienne;Leca, Julie;Vasseur, Sophie
胰腺导管腺癌是最难治、最致命的癌症之一。肿瘤显示的血管密度降低不仅有利于其对化疗的抵抗，而且由于随之而来的高度缺氧而参与了其侵袭性。确实很明显，低氧增加了对恶性细胞的选择性压力，这些细胞必须产生适应性的代谢反应，以达到其能量和生物合成的需求。在这里，使用定义明确的胰腺癌小鼠模型，我们报告了胰腺导管腺癌的缺氧区主要由具有上皮-间充质转化特征的上皮细胞和表达糖酵解标志的上皮细胞组成，这两个特征与肿瘤侵袭性相关。我们还表明，低氧增加了胰腺癌细胞从氧化磷酸化到乳酸产生的“糖酵解”转换，我们还证明了低氧癌细胞乳酸外流的增加有利于正常氧癌细胞的生长。此外，我们还发现低氧胰腺肿瘤细胞的谷氨酰胺代谢是其生存所必需的。代谢的葡萄糖和谷氨酰胺汇聚到一个共同的途径，称为己糖胺生物合成途径，允许O-连接的N-乙酰氨基葡萄糖修饰蛋白质。在这里，我们报告了缺氧增加了己糖胺生物合成途径基因的转录和O-糖基化蛋白的水平，蛋白质的O-连接N-乙酰氨基葡萄糖基化是低氧胰腺癌细胞生存所必需的过程。我们的结果表明，低氧驱动的代谢适应过程，如高糖酵解率和己糖胺生物合成途径的激活，有利于低氧和常氧癌细胞的存活，并与胰腺导管腺癌的侵袭性相关。
Pancreatic ductal adenocarcinoma is one of the most intractable and fatal cancer. The decreased blood vessel density displayed by this tumor not only favors its resistance to chemotherapy but also participates in its aggressiveness due to the consequent high degree of hypoxia. It is indeed clear that hypoxia promotes selective pressure on malignant cells that must develop adaptive metabolic responses to reach their energetic and biosynthetic demands. Here, using a well-defined mouse model of pancreatic cancer, we report that hypoxic areas from pancreatic ductal adenocarcinoma are mainly composed of epithelial cells harboring epithelial-mesenchymal transition features and expressing glycolytic markers, two characteristics associated with tumor aggressiveness. We also show that hypoxia increases the "glycolytic" switch of pancreatic cancer cells from oxydative phosphorylation to lactate production and we demonstrate that increased lactate efflux from hypoxic cancer cells favors the growth of normoxic cancer cells. In addition, we show that glutamine metabolization by hypoxic pancreatic tumor cells is necessary for their survival. Metabolized glucose and glutamine converge toward a common pathway, termed hexosamine biosynthetic pathway, which allows O-linked N-acetylglucosamine modifications of proteins. Here, we report that hypoxia increases transcription of hexosamine biosynthetic pathway genes as well as levels of O-glycosylated proteins and that O-linked N-acetylglucosaminylation of proteins is a process required for hypoxic pancreatic cancer cell survival. Our results demonstrate that hypoxia-driven metabolic adaptive processes, such as high glycolytic rate and hexosamine biosynthetic pathway activation, favor hypoxic and normoxic cancer cell survival and correlate with pancreatic ductal adenocarcinoma aggressiveness.