Overexpression of ubiquitous mitochondrial creatine kinase (uMtCK) accelerates tumor growth by inhibiting apoptosis of breast cancer cells and is associated with a poor prognosis in breast cancer patients
Overexpression of ubiquitous mitochondrial creatine kinase (uMtCK) accelerates tumor growth by inhibiting apoptosis of breast cancer cells and is associated with a poor prognosis in breast cancer patients
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普遍存在的线粒体肌酸激酶（uMtCK）的过度表达通过抑制乳腺癌细胞凋亡来加速肿瘤生长，并与乳腺癌患者的不良预后相关
DOI：
10.1016/j.bbrc.2012.08.147
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发表时间：
2012-10-12
影响因子：
3.1
通讯作者：
Fu, Li
中科院分区：
文献类型：
--
作者：
Qian, Xiao-Long;Li, Ya-Qing;Fu, Li
背景资料：普遍存在的线粒体肌酸激酶（uMtCK）是肌酸激酶（CK）的线粒体同工酶，是细胞能量稳态的中央控制器。据报道，uMtCK的过表达与几种肿瘤的不良预后相关。本研究的目的是评估其与乳腺癌（BCa）的相关性，并进一步探讨其潜在的mechanism.Method：我们首先检测uMtCK表达的人BCa组织免疫组化和评估与患者的预后。然后，我们评估了几种人BCa细胞系在拥挤和正常条件下培养的uMtCK表达。建立了两个稳定的高表达uMtCK的MDA-MB-231细胞系克隆后，测定这些克隆中的细胞生长、凋亡和线粒体凋亡途径蛋白表达。结果：在55例乳腺浸润性导管癌中，uMtCK阳性表达率为85.5%（47/55），未另作说明（IDC-NOS）。BCa组织中的表达与患者的无进展生存期（PFS; P = 0.019）和总生存期（OS; P = 0.022）降低显著相关。UMtCK基因转染的MDA-MB-231细胞克隆中，UMtCK表达上调，凋亡细胞数明显减少（P < 0.01）。稳定的线粒体膜电位（Δ Psim）和下调的细胞色素c（cyt c）和激活的caspase 9，线粒体凋亡途径蛋白的两个组成部分，也确定在相同的克隆细胞拥挤的培养。体内实验表明，转染过表达uMtCK的肿瘤细胞能加速裸鼠肿瘤的生长，沿着动物体重的下降，并显著降低肿瘤细胞的凋亡指数（AI）（P < 0.001）。体内和体外证据表明，uMtCK过表达通过稳定Δ Psim和下调线粒体凋亡途径蛋白来抑制肿瘤细胞凋亡，从而促进肿瘤生长。针对uMtCK表达的治疗药物的探索对BCa患者可能具有实用价值。(C)2012 Elsevier Inc. All rights reserved.
Background: Ubiquitous mitochondrial creatine kinase (uMtCK), a mitochondrial isoenzyme of creatine kinase (CK), is a central controller of cellular energy homeostasis. Overexpression of uMtCK has been reported to be associated with a poor prognosis for several tumors. The aim of this study was to assess its association with breast cancer (BCa) and to further investigate its underlying mechanisms.Method: We first detected uMtCK expression by immunohistochemistry in human BCa tissues and assessed the association with the prognosis of patients. We then evaluated uMtCK expression in crowded and normal condition cultures of several human BCa cell lines. After two stable clones of the MDA-MB-231 cell line with high expression of uMtCK were established, cell growth, apoptosis and mitochondrial apoptotic pathway protein expression were measured in these clones. Finally, tumorigenicity of the above cells was assessed using nude mice to explore the relationship between uMtCK expression and tumor progression.Results: uMtCK expression was detected in 85.5% (47 of 55) of the invasive ductal carcinomas of breast tissue, not otherwise specified (IDC-NOS). Expression in BCa tissue was significantly associated with reduced progression-free survival (PFS; P = 0.019) and overall survival (OS; P = 0.022) of the patients. Up-regulation of uMtCK expression was identified in crowded BCa cells in culture, and the number of apoptotic cells was significantly decreased in uMtCK transfected MDA-MB-231 cell clones (P < 0.01). Stabilization of the mitochondrial membrane potential (Delta Psi m) and down regulation of cytochrome c (cyt c) and activated caspase 9, two components of mitochondrial apoptotic pathway proteins, were also identified in the same clones when cells were crowded in culture. In vivo studies revealed that the transfected tumor cells with uMtCK overexpression induced faster tumor growth in nude mice, along with accelerated animal body weight loss and a significantly lower tumor apoptotic index (AI) (P < 0.001).Conclusion: The results indicated that uMtCK expression is associated with a poor prognosis in BCa and might serve as a tumor marker. In vivo and In vitro evidence suggests that uMtCK overexpression promotes tumor growth by inhibiting apoptosis of tumor cells through stabilizing Delta Psi m and down regulating mitochondrial apoptotic pathway proteins. Exploration of therapeutic agents targeting the expression of uMtCK may have practical value for BCa patients. (C) 2012 Elsevier Inc. All rights reserved.