5′-AMP-activated Protein Kinase (AMPK) Supports the Growth of Aggressive Experimental Human Breast Cancer Tumors
5′-AMP-activated Protein Kinase (AMPK) Supports the Growth of Aggressive Experimental Human Breast Cancer Tumors
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DOI：
10.1074/jbc.m114.576371
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发表时间：
2014-08-15
影响因子：
4.8
通讯作者：
Boros, Laszlo G.
中科院分区：
文献类型：
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作者：
Laderoute, Keith R.;Calaoagan, Joy M.;Boros, Laszlo G.
肿瘤的快速生长可以建立代谢应激微环境，激活5'-腺苷酸活化蛋白激酶（AMPK），一种普遍存在的ATP稳态调节剂。在此之前，我们研究了AMPK在由hras转化的小鼠胚胎成纤维细胞制备的实验肿瘤生长中的重要性，以及在大鼠神经癌模型中原发性脑肿瘤的发展。在这里，我们使用AMPK活性被敲低的三阴性人乳腺癌细胞来研究AMPK对实验性肿瘤生长和核心葡萄糖代谢的贡献。我们发现AMPK支持MDA-MB-231和DU4475乳腺癌细胞制备的快速生长的原位肿瘤的生长，但对这些细胞在培养中的增殖或存活没有影响。我们使用[C-13]葡萄糖示踪剂进行体外和体内代谢分析，研究AMPK对具有Warburg代谢表型的MDA-MB-231细胞核心葡萄糖代谢的贡献；这些实验表明AMPK部分通过正向调节糖酵解和非氧化戊糖磷酸循环来支持肿瘤糖代谢。我们还发现AMPK在MDA-MB-231肿瘤中的活性可以系统性地扰乱敏感的正常组织（肝脏和胰腺）的葡萄糖稳态。总之，我们的研究结果表明，AMPK对侵袭性实验肿瘤生长的贡献具有关键的微环境成分，涉及核心葡萄糖代谢的特定调节。
Rapid tumor growth can establish metabolically stressed microenvironments that activate 5'-AMP-activated protein kinase (AMPK), a ubiquitous regulator of ATP homeostasis. Previously, we investigated the importance of AMPK for the growth of experimental tumors prepared from HRAS-transformed mouse embryo fibroblasts and for primary brain tumor development in a rat model of neurocarcinogenesis. Here, we used triple-negative human breast cancer cells in which AMPK activity had been knocked down to investigate the contribution of AMPK to experimental tumor growth and core glucose metabolism. We found that AMPK supports the growth of fast-growing orthotopic tumors prepared from MDA-MB-231 and DU4475 breast cancer cells but had no effect on the proliferation or survival of these cells in culture. We used in vitro and in vivo metabolic profiling with [C-13] glucose tracers to investigate the contribution of AMPK to core glucose metabolism in MDA-MB-231 cells, which have a Warburg metabolic phenotype; these experiments indicated that AMPK supports tumor glucose metabolism in part through positive regulation of glycolysis and the nonoxidative pentose phosphate cycle. We also found that AMPK activity in the MDA-MB-231 tumors could systemically perturb glucose homeostasis in sensitive normal tissues (liver and pancreas). Overall, our findings suggest that the contribution of AMPK to the growth of aggressive experimental tumors has a critical microenvironmental component that involves specific regulation of core glucose metabolism.