摘要
恶性黑色素瘤是最致命的癌症之一,它具有侵袭能力强、易转移以及对多种化疗药物有治疗抵抗作用等特点。患恶性黑色素瘤的风险伴随着与氧化磷酸化能量代谢异常,而这个过程主要是在线粒体中的复合体上完成。复合体I是线粒体中完成氧化磷酸化过程中的第一个复合体,也是线粒体中最大的复合体酶。CD147是一个主要在细胞膜上表达的跨膜糖蛋白,同时也可在肿瘤细胞的细胞质中存在。我们发现与初期相比,恶性黑色素瘤转移后CD147变为在细胞质中表达。同时我们也发现在A375线粒体片段中CD147的高表达。酵母双杂交实验证实NDUFS6(可编译氧化呼吸链复合体I的一个亚基)与CD147结合以后作为一个储备形式,以及A375细胞中CD147的消耗将显著降低复合体I的活性。我们同时也发现CD147增强了A375细胞线粒体受到小檗碱损伤后的存活能力,可以通过一个线粒体依赖性旁路避免A375细胞的凋亡。这个发现由在A375细胞培养基中添加外源性基因Bcl-2所证实。总之,我们的研究证实了CD147在人类恶性黑色素瘤线粒体细胞中的存在。这些研究表明CD147或将调节复合体I的活性,并通过与线粒体NDUFS6的结合阻止细胞的凋亡。我们的发现重新审视了CD147的功能,并且它的证实将为肿瘤的药物靶向治疗提供新依据。
关键词: 细胞凋亡,CD147,复合体I活性,黑色素瘤,线粒体,NDUFS6.
Current Molecular Medicine
Title:CD147 Interacts with NDUFS6 in Regulating Mitochondrial Complex I Activity and the Mitochondrial Apoptotic Pathway in Human Malignant Melanoma Cells
Volume: 14 Issue: 10
Author(s): Z. Luo, W. Zeng, W. Tang, T. Long, J. Zhang, X. Xie, Y. Kuang, M. Chen, J. Su and X. Chen
Affiliation:
关键词: 细胞凋亡,CD147,复合体I活性,黑色素瘤,线粒体,NDUFS6.
摘要: Malignant melanoma (MM) is one of the most lethal tumors and is characterized by high invasiveness, frequent metastasis, and resistance to chemotherapy. The risk of metastatic MM is accompanied by disordered energy metabolism involving the oxidative phosphorylation (OXPHOS) process, which is largely carried out in mitochondrial complexes. Complex I is the first and largest mitochondrial enzyme complex associated with this process. CD147 is a transmembrane glycoprotein mainly expressed on the cell surface, and also appears in the cytoplasm in some tumors. We found that CD147 is often translocated to the cytoplasm in metastatic MM specimens as compared to primary MM. We also demonstrated high expression of CD147 in isolated mitochondrial fractions of A375 cells. The yeast two-hybrid (Y2H) assay identified NDUFS6 (which encodes a subunit of mitochondrial respiratory chain complex I) as a candidate that interacts with CD147 and depletion of CD147 in A375 cells significantly decreased complex I enzyme activity. We also showed that CD147 increased the viability of A375 cells exposed to berberine-induced mitochondrial damage, and protected them from apoptosis through a mitochondrial-dependent pathway. This finding was confirmed by adding exogenous Bcl-2 to A375 cell cultures. In summary, our results identify the existence of CD147 in human melanoma cell mitochondria. They indicate that CD147 appears to regulate complex I activity and apoptosis in MM by interacting with mitochondrial NDUFS6. Our findings provide new insight into the function of CD147 and identify it as a promising therapeutic target in melanoma through disruption of the energy metabolism.
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Z. Luo, W. Zeng, W. Tang, T. Long, J. Zhang, X. Xie, Y. Kuang, M. Chen, J. Su and X. Chen , CD147 Interacts with NDUFS6 in Regulating Mitochondrial Complex I Activity and the Mitochondrial Apoptotic Pathway in Human Malignant Melanoma Cells, Current Molecular Medicine 2014; 14 (10) . https://dx.doi.org/10.2174/1566524014666141202144601
DOI https://dx.doi.org/10.2174/1566524014666141202144601 |
Print ISSN 1566-5240 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5666 |
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