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首页> 外文期刊>Cellular Signalling >Conjugated linoleic acid-induced apoptosis in mouse mammary tumor cells is mediated by both G protein coupled receptor-dependent activation of the AMP-activated protein kinase pathway and by oxidative stress
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Conjugated linoleic acid-induced apoptosis in mouse mammary tumor cells is mediated by both G protein coupled receptor-dependent activation of the AMP-activated protein kinase pathway and by oxidative stress

机译：共轭亚油酸诱导的小鼠乳腺肿瘤细胞凋亡是由AMP激活的蛋白激酶途径的G蛋白偶联受体依赖性激活和氧化应激介导的

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Conjugated linoleic acid (CLA) has shown chemopreventive activity in several tumorigenesis models, in part through induction of apoptosis. We previously demonstrated that the t10,c12 isomer of CLA induced apoptosis of TM4t mouse mammary tumor cells through both mitochondrial and endoplasmic reticulum (ER) stress pathways, and that the AMP-activated protein kinase (AMPK) played a critical role in the apoptotic effect. In the current study, we focused on the upstream pathways by which AMPK was activated, and additionally evaluated the contributing role of oxidative stress to apoptosis. CLA-induced activation of AMPK and/or induction of apoptosis were inhibited by infection of TM4t cells with an adenovirus expressing a peptide which blocks the interaction between the G protein coupled receptor (GPCR) and Gα_q, by the phospholipase C (PLC) inhibitor U73122, by the inositol trisphosphate (IP_3) receptor inhibitor 2-APB, by the calcium/calmodulin-dependent protein kinase kinase α (CaMKK) inhibitor STO-609 and by the intracellular Ca~(2+) chelator BAPTA-AM. This suggests that t10,c12-CLA may exert its apoptotic effect by stimulating GPCR through Gα_q signaling, activation of phosphatidylinositol-PLC, followed by binding of the PLC-generated IP_3 to its receptor on the ER, triggering Ca~(2+) release from the ER and finally stimulating the CaMKK-AMPK pathway. t10,c12-CLA also increased oxidative stress and lipid peroxidation, and antioxidants blocked its apoptotic effect, as well as the CLA-induced activation of p38 MAPK, a downstream effector of AMPK. Together these data elucidate two major pathways by which t10,c12-CLA induces apoptosis, and suggest a point of intersection of the two pathways both upstream and downstream of AMPK.
机译：共轭亚油酸（CLA）在几种肿瘤发生模型中显示出化学预防活性，部分是通过诱导细胞凋亡。我们以前证明CLA的t10，c12异构体通过线粒体和内质网（ER）应激途径诱导TM4t小鼠乳腺肿瘤细胞凋亡，并且AMP激活的蛋白激酶（AMPK）在细胞凋亡效应中起关键作用。在当前的研究中，我们集中于激活AMPK的上游途径，并另外评估了氧化应激对细胞凋亡的作用。 TM4t细胞被表达磷脂酰腺苷C（PLC）抑制剂U73122阻断G蛋白偶联受体（GPCR）和Gα_q之间相互作用的肽段的腺病毒感染，抑制了CLA诱导的AMPK激活和/或凋亡诱导。 ，肌醇三磷酸（IP_3）受体抑制剂2-APB，钙/钙调蛋白依赖性蛋白激酶激酶α（CaMKK）抑制剂STO-609和细胞内Ca〜（2+）螯合剂BAPTA-AM。这表明t10，c12-CLA可能通过以下方式发挥其凋亡作用：通过Gα_q信号刺激GPCR，激活磷脂酰肌醇-PLC，然后将PLC生成的IP_3与其在ER上的受体结合，触发Ca〜（2+）释放。从ER中获得，并最终刺激CaMKK-AMPK途径。 t10，c12-CLA还增加了氧化应激和脂质过氧化作用，抗氧化剂阻止了它的凋亡作用，以及CLA诱导的AMPK下游效应物p38 MAPK的激活。这些数据共同阐明了t10，c12-CLA诱导凋亡的两个主要途径，并提出了AMPK上游和下游这两个途径的交叉点。

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