The HMGB1/RAGE inflammatory pathway promotes pancreatic tumor growth by regulating mitochondrial bioenergetics
The HMGB1/RAGE inflammatory pathway promotes pancreatic tumor growth by regulating mitochondrial bioenergetics
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DOI：
10.1038/onc.2012.631
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发表时间：
2014-01-30
期刊：
影响因子：
8
通讯作者：
Zeh, H. J.
中科院分区：
文献类型：
--
作者：
Kang, R.;Tang, D.;Zeh, H. J.
肿瘤细胞需要增加的三磷酸腺苷（ATP）来支持凋亡和增殖。在肿瘤细胞中调节这一过程的确切机制尚不清楚。在这里，我们表明，晚期糖基化终产物（AGEs）受体及其主要配体之一，高迁移率族蛋白1（HMGB 1），是肿瘤内最佳线粒体功能所必需的。我们发现，在培养的肿瘤细胞以及原发性肿瘤的线粒体中，存在着这种蛋白。HMGB 1和HMGB 1协同增强肿瘤细胞线粒体复合物I活性、ATP产生、肿瘤细胞增殖和迁移。缺乏抑制或抑制HMGB 1的释放减少了ATP的产生，并在体外和体内减缓了肿瘤的生长。这些发现首次将HMGB 1-β通路与生物能量学的变化联系起来。此外，我们的观察结果提供了一种新的机制，在肿瘤微环境中，坏死和炎症促进肿瘤进展。
Tumor cells require increased adenosine triphosphate (ATP) to support anabolism and proliferation. The precise mechanisms regulating this process in tumor cells are unknown. Here, we show that the receptor for advanced glycation endproducts (RAGE) and one of its primary ligands, high-mobility group box 1 (HMGB1), are required for optimal mitochondrial function within tumors. We found that RAGE is present in the mitochondria of cultured tumor cells as well as primary tumors. RAGE and HMGB1 coordinately enhanced tumor cell mitochondrial complex I activity, ATP production, tumor cell proliferation and migration. Lack of RAGE or inhibition of HMGB1 release diminished ATP production and slowed tumor growth in vitro and in vivo. These findings link, for the first time, the HMGB1-RAGE pathway with changes in bioenergetics. Moreover, our observations provide a novel mechanism within the tumor microenvironment by which necrosis and inflammation promote tumor progression.