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首页> 美国卫生研究院文献>Proceedings of the National Academy of Sciences of the United States of America >Strengthened glycolysis under hypoxia supports tumor symbiosis and hexosamine biosynthesis in pancreatic adenocarcinoma
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Strengthened glycolysis under hypoxia supports tumor symbiosis and hexosamine biosynthesis in pancreatic adenocarcinoma

机译：低氧条件下加强糖酵解可支持胰腺腺癌的肿瘤共生和己糖胺的生物合成

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摘要

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.
机译：胰腺导管腺癌是最难治且致命的癌症之一。该肿瘤表现出的降低的血管密度不仅有利于其对化学疗法的抗性，而且由于随之而来的高度缺氧而参与其侵袭性。确实很明显，缺氧促进了对恶性细胞的选择性压力，恶性细胞必须发展适应性代谢反应才能达到其能量和生物合成需求。在这里，使用定义明确的胰腺癌小鼠模型，我们报道了来自胰腺导管腺癌的低氧区域主要由上皮细胞组成，这些上皮细胞具有上皮-间质转化特征并表达糖酵解标记物，这是与肿瘤侵袭性相关的两个特征。我们还表明，低氧增加了胰腺癌细胞从氧化磷酸化到乳酸生成的“糖酵解”转换，并且我们证明了缺氧癌细胞的乳酸外排增加有利于常氧癌细胞的生长。此外，我们表明低氧胰腺肿瘤细胞的谷氨酰胺代谢对于其生存是必要的。代谢的葡萄糖和谷氨酰胺会汇聚到一条称为己糖胺生物合成途径的通用途径，该途径允许O-联的N-乙酰氨基葡萄糖修饰蛋白质。在这里，我们报道缺氧增加了己糖胺生物合成途径基因的转录以及O-糖基化蛋白的水平，O-蛋白的N-乙酰基葡萄糖酰胺化是缺氧胰腺癌细胞存活所需要的过程。我们的结果表明，低氧驱动的代谢适应性过程（例如高糖酵解速率和己糖胺生物合成途径激活）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。

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