Drexler Konstantin, Schwertner Barbara, Haerteis Silke, Aung Thiha, Berneburg Mark, Geissler Edward K, Mycielska Maria E, Haferkamp Sebastian
Department of Dermatology, University Medical Center, 93053 Regensburg, Germany.
Institute for Molecular and Cellular Anatomy, University of Regensburg, 93053 Regensburg, Germany.
Cancers (Basel). 2022 Jul 14;14(14):3425. doi: 10.3390/cancers14143425.
Merkel cell carcinoma (MCC) is a rare but highly aggressive tumor of the skin with a poor prognosis. The factors driving this cancer must be better understood in order to discover novel targets for more effective therapies. In the search for targets, we followed our interest in citrate as a central and critical metabolite linked to fatty acid synthesis in cancer development. A key to citrate uptake in cancer cells is the high expression of the plasma membrane citrate transporter (pmCiC), which is upregulated in the different adenocarcinoma types tested so far. In this study, we show that the pmCiC is also highly expressed in Merkel cell carcinoma cell lines by western blot and human tissues by immunohistochemistry staining. In the presence of extracellular citrate, MCC cells show an increased proliferation rate in vitro; a specific pmCiC inhibitor (Na-gluconate) blocks this citrate-induced proliferation. Furthermore, the 3D in vivo Chick Chorioallantoic Membrane (CAM) model showed that the application of Na-gluconate also decreases Merkel cell carcinoma growth. Based on our results, we conclude that pmCiC and extracellular citrate uptake should be considered further as a potential novel target for the treatment of Merkel cell carcinoma.
默克尔细胞癌（MCC）是一种罕见但侵袭性很强的皮肤肿瘤，预后较差。为了发现更有效治疗方法的新靶点，必须更好地了解驱动这种癌症的因素。在寻找靶点的过程中，我们关注到柠檬酸盐作为一种在癌症发展中与脂肪酸合成相关的核心且关键的代谢物。癌细胞摄取柠檬酸盐的一个关键是质膜柠檬酸盐转运体（pmCiC）的高表达，到目前为止，在测试的不同腺癌类型中它都上调。在这项研究中，我们通过蛋白质印迹法表明pmCiC在默克尔细胞癌细胞系中也高表达，通过免疫组织化学染色表明在人体组织中也高表达。在存在细胞外柠檬酸盐的情况下，MCC细胞在体外显示出增殖率增加；一种特异性的pmCiC抑制剂（葡萄糖酸钠）可阻断这种柠檬酸盐诱导的增殖。此外，三维体内鸡胚绒毛尿囊膜（CAM）模型显示，葡萄糖酸钠的应用也会减少默克尔细胞癌的生长。基于我们的结果，我们得出结论，pmCiC和细胞外柠檬酸盐摄取应进一步被视为治疗默克尔细胞癌的潜在新靶点。
