Mitochondrial creatine kinase 1 regulates the cell cycle in non-small cell lung cancer via activation of cyclin-dependent kinase 4.
Mitochondrial creatine kinase 1 regulates the cell cycle in non-small cell lung cancer via activation of cyclin-dependent kinase 4.
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DOI：
10.1186/s12931-023-02417-2
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发表时间：
2023-04-15
影响因子：
5.8
通讯作者：
中科院分区：
文献类型：
--
作者：
非小细胞肺癌(NSCLC)是世界上最常见的恶性肿瘤的主要类型。已有研究表明，线粒体肌酸激酶1(CKMT1)在非小细胞肺癌中表达异常，但其作用机制尚不清楚。因此，本研究旨在阐明CKMT1在非小细胞肺癌中的可能机制，为CKMT1的临床应用提供理论依据。通过分析GEO数据集和使用体外和体内模型评估CKMT1在NSCLC中的功能。用蛋白质质谱仪检测与CKMT1相互作用的蛋白质，用免疫共沉淀(Co-IP)和GST-Pull Down实验验证蛋白质之间的相互作用。免疫荧光(IF)法检测CKMT1在细胞中的功能定位。通过体内和体外联合实验，分析CKMT1表达水平对紫杉醇(TAX)治疗NSCLC疗效的影响。CKMT1在NSCLC中表达增加，在体内外均能促进NSCLC细胞的增殖。CKMT1基因敲除后，G0/G1期细胞比例明显增加，S期细胞比例明显降低，表明细胞周期停滞于G1期。从机制上讲，细胞周期蛋白依赖的蛋白4(CDK4)与CKMT1相互作用，关键的结合区域集中在CKMT1的水解区以及CDK4的N-端和C-端。部分CDK4蛋白与线粒体上的CKMT1共定位并相互作用，其磷酸化水平受CKMT1的调控。因此，降低CKMT1的表达水平可以增强G2/M期细胞周期拮抗剂TAX在体内外对NSCLC的抗肿瘤作用。CKMT1可与线粒体中的CDK4相互作用，调节CDK4的磷酸化水平，从而促进NSCLC细胞的增殖和细胞周期的转变。CKMT1可能成为提高TAX化疗敏感性的潜在靶点。网上版载有补充材料，可在10.1186/s12931-023-02417-2查阅。
Non-small cell lung cancer (NSCLC) is the main type of the most common malignant tumor in the world. Previous studies have shown that the expression level of mitochondrial creatine kinase 1 (CKMT1) is abnormal in NSCLC, but the mechanism of its effect remains unclear. Therefore, in this study, we intend to clarify the potential mechanism of CKMT1 in NSCLC and provide the theoretical basis for the clinical application of CKMT1. The function of CKMT1 in NSCLC was identified by analyzing the GEO dataset and evaluating using in vitro and in vivo models. Protein mass spectrometry was used to find proteins interacting with CKMT1, and Co-immunoprecipitation (Co-IP) and GST-pull down experiments were used to verify the interaction between proteins. The immunofluorescence (IF) assay was used to explore the functional position of CKMT1 in cells. The effect of CKMT1 expression level on the efficacy of paclitaxel (TAX) in the treatment of NSCLC was analyzed by a combined TAX experiment in vivo and in vitro. CKMT1 expression was increased in NSCLC and CKMT1 promoted the proliferation of NSCLC cells in vitro and in vivo. CKMT1 knockdown resulted in a significantly increased G0/G1 fraction and decreased S phase cell fraction, indicating G1 phase arrest. Mechanically, the cyclin-dependent kinase 4 (CDK4) was identified to interact with CKMT1, and the crucial binding areas were focused on the DH domain of CKMT1 and the N- and C-terminal of CDK4. A fraction of the CDK4 proteins colocalize and interact with the CKMT1 at mitochondria, the level of phosphorylated CDK4 was regulated by CKMT1. Hence, the decrease in CKMT1 expression level could increase the antitumor effect of G2/M cell cycle antagonist-TAX in NSCLC in vitro and in vivo. CKMT1 could interact with CDK4 in mitochondria and regulate the phosphorylated level of CDK4, thus contributing to the proliferation and cell cycle transition of NSCLC cells. And CKMT1 could be a potential target to improve the sensitivity of chemotherapy based on TAX. The online version contains supplementary material available at 10.1186/s12931-023-02417-2.
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影响因子：
5.8
作者：
Li M;Liu H;Li J;Guo S;Lv Y
通讯作者：
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影响因子：
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作者：
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影响因子：
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作者：
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通讯作者：
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DOI：
10.1002/hed.24232
发表时间：
2016-04-01
影响因子：
2.9
作者：
Angel Pavon, Miguel;Parreno, Matilde;Mangues, Ramon
通讯作者：
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