Dysregulation of ezrin phosphorylation prevents metastasis and alters cellular metabolism in osteosarcoma.
Dysregulation of ezrin phosphorylation prevents metastasis and alters cellular metabolism in osteosarcoma.
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DOI：
10.1158/0008-5472.can-11-0210
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发表时间：
2012-02-15
期刊：
影响因子：
11.2
通讯作者：
Khanna C
中科院分区：
文献类型：
--
作者：
Ren L;Hong SH;Chen QR;Briggs J;Cassavaugh J;Srinivasan S;Lizardo MM;Mendoza A;Xia AY;Avadhani N;Khan J;Khanna C
Ezrin将质膜与肌动蛋白细胞骨架连接起来，在几种人类癌症的转移过程中起着关键作用，然而，其作用的确切机制基础尚不清楚。在这里，我们定义了在骨肉瘤转移过程中发生的活性（磷酸化开放）和非活性（去磷酸化封闭）Ezrin形式之间的转变。在我们对这些构象的评估中，我们表达了开放的（拟磷型T567D）或关闭的（缺磷型T567A） Ezrin的c端突变形式，并将其生物学特性与骨肉瘤细胞中全长野生型Ezrin进行了比较。出乎意料的是，表达开放、活性Ezrin的细胞既不能形成原发原位肿瘤，也不能形成肺转移瘤。相反，表达封闭、失活Ezrin的细胞也缺乏转移，但其原发肿瘤生长能力不受影响。通过对肺中单个转移细胞的成像，我们发现表达开放或关闭Ezrin的细胞在到达肺后早期显示出增加的凋亡水平。基因表达分析表明，与碳水化合物和氨基酸代谢功能相关的基因失调。特别是，表达封闭、失活Ezrin的细胞表现出乳酸生成和基础或atp依赖性氧消耗的减少。总之，我们的研究结果表明，控制该蛋白结构转变的氨基酸T567上Ezrin磷酸化的动态调节在肿瘤进展和转移中起关键作用，可能部分通过改变细胞代谢。
Ezrin links the plasma membrane to the actin cytoskeleton where it plays a pivotal role in the metastatic progression of several human cancers, however, the precise mechanistic basis for its role remains unknown. Here we define transitions between active (phosphorylated open) and inactive (dephosphorylated closed) forms of Ezrin that occur during metastatic progression in osteosarcoma. In our evaluation of these conformations we expressed C-terminal mutant forms of Ezrin that are open (phosphomimetic T567D) or closed (phosphodeficient T567A) and compared their biological characteristics to full length wild-type Ezrin in osteosarcoma cells. Unexpectedly, cells expressing open, active Ezrin could form neither primary orthotopic tumors nor lung metastases. In contrast, cells expressing closed, inactive Ezrin were also deficient in metastasis but were unaffected in their capacity for primary tumor growth. By imaging single metastatic cells in the lung, we found that cells expressing either open or closed Ezrin displayed increased levels of apoptosis early after their arrival in the lung. Gene expression analysis suggested dysregulation of genes that are functionally linked to carbohydrate and amino acid metabolism. In particular, cells expressing closed, inactive Ezrin exhibited reduced lactate production and basal or ATP-dependent oxygen consumption. Collectively, our results suggest that dynamic regulation of Ezrin phosphorylation at amino acid T567 that controls structural transitions of this protein plays a pivotal role in tumor progression and metastasis, possibly in part by altering cellular metabolism.