7-amino carboxycoumarin 2 可通过 MPC1 抑制乳酸诱导的口腔癌和乳腺癌细胞上皮细胞向间质转化。

IF 3.3 3区 生物学 Q3 CELL BIOLOGY
Sheikh Mohammad Umar, Arundhathi J. R. Dev, Akanksha Kashyap, Meetu Rathee, Shyam S. Chauhan, Atul Sharma, Chandra Prakash Prasad
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引用次数: 0

摘要

乳酸盐是一种对肿瘤侵袭性起重要作用的代谢产物。癌细胞通过线粒体氧化磷酸化(或 OXPHOS)吸收肿瘤微环境(TME)中的乳酸盐作为能量资源。在本研究中,我们利用在线荟萃分析工具证明,在口腔鳞状癌细胞(OSCCs)中,糖酵解和 OXPHOS 的调控基因与乳腺癌一样被过度表达。为了进行实验证明,我们用 L-乳酸钠处理了 OSCC 细胞系(SCC4)和乳腺癌细胞(MDA-MB-231),并分析了其对 EMT 和迁移变化的影响。为了对乳酸代谢进行治疗干预,我们使用了AZD3965(一种MCT1抑制剂)和7ACC2(一种MPC抑制剂)。与乳腺癌一样,口腔癌组织也显示出 12 个基因的转录量增加,这些基因以前曾被证明与糖酵解和 OXPHOS 有关。我们通过实验证明,L-乳酸盐处理可诱导间质标记和癌细胞的迁移,而 MPC 抑制剂(即 7ACC2 )可显著中和这种作用。而 AZD3965 对 EMT 状态的影响则不明显。此外,我们还发现乳酸处理会增加两种癌细胞中 MPC1 的表达,这可能是高乳酸环境中的癌细胞对 7ACC2 更为敏感的原因。总之,我们目前的研究结果表明,细胞外乳酸能正向调节癌细胞中 MPC1 蛋白的表达,从而提出了将 7ACC2 作为抑制恶性氧化性癌症的潜在替代疗法的概念。未来的临床前研究有必要对本研究结果进行验证。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
7-amino carboxycoumarin 2 inhibits lactate induced epithelial-to-mesenchymal transition via MPC1 in oral and breast cancer cells

Lactate is an oncometabolite that play important role in tumor aggressiveness. Lactate from the tumor microenvironment (TME) is taken up by cancer cells as an energy resource via mitochondrial oxidative phosphorylation (or OXPHOS). In the present study, by using an online meta-analysis tool we demonstrated that in oral squamous cancer cells (OSCCs) glycolytic and OXPHOS governing genes are overexpressed, like in breast cancer. For experimental demonstration, we treated the OSCC cell line (SCC4) and breast cancer cells (MDA-MB-231) with sodium L-lactate and analyzed its effects on changes in EMT and migration. For the therapeutic intervention of lactate metabolism, we used AZD3965 (an MCT1 inhibitor), and 7ACC2 (an MPC inhibitor). Like breast cancer, oral cancer tissues showed increased transcripts of 12 genes that were previously shown to be associated with glycolysis and OXPHOS. We experimentally demonstrated that L-lactate treatment induced mesenchymal markers and migration of cancer cells, which was significantly neutralized by MPC inhibitor that is, 7ACC2. Such an effect on EMT status was not observed with AZD3965. Furthermore, we showed that lactate treatment increases the MPC1 expression in both cancer cells, and this might be the reason why cancer cells in the high lactate environment are more sensitive to 7ACC2. Overall, our present findings demonstrate that extracellular lactate positively regulates the MPC1 protein expression in cancer cells, thereby putting forward the notion of using 7ACC2 as a potential therapeutic alternative to inhibit malignant oxidative cancers. Future preclinical studies are warranted to validate the present findings.

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来源期刊
Cell Biology International
Cell Biology International 生物-细胞生物学
CiteScore
7.60
自引率
0.00%
发文量
208
审稿时长
1 months
期刊介绍: Each month, the journal publishes easy-to-assimilate, up-to-the minute reports of experimental findings by researchers using a wide range of the latest techniques. Promoting the aims of cell biologists worldwide, papers reporting on structure and function - especially where they relate to the physiology of the whole cell - are strongly encouraged. Molecular biology is welcome, as long as articles report findings that are seen in the wider context of cell biology. In covering all areas of the cell, the journal is both appealing and accessible to a broad audience. Authors whose papers do not appeal to cell biologists in general because their topic is too specialized (e.g. infectious microbes, protozoology) are recommended to send them to more relevant journals. Papers reporting whole animal studies or work more suited to a medical journal, e.g. histopathological studies or clinical immunology, are unlikely to be accepted, unless they are fully focused on some important cellular aspect. These last remarks extend particularly to papers on cancer. Unless firmly based on some deeper cellular or molecular biological principle, papers that are highly specialized in this field, with limited appeal to cell biologists at large, should be directed towards journals devoted to cancer, there being very many from which to choose.
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