Bosserhoff Anja K, Ellmann Lisa, Quast Annika S, Eberle Juergen, Boyle Glen M, Kuphal Silke
Institute of Pathology, Molecular Pathology, University of Regensburg, Regensburg, Germany.
Mol Carcinog. 2014 Aug;53(8):635-47. doi: 10.1002/mc.22018. Epub 2013 Apr 26.
An understanding of signaling pathways is a basic requirement for the treatment of melanoma. Currently, kinases are at the center of melanoma therapies. According to our research, additional alternative molecules are equally important for development of melanoma. In this regard, cancer progression is, among other factors, driven by an altered adhesion via cadherins. For instance, the de-regulated expression of the adhesion molecule T-cadherin is found in various cancer types, including melanoma, and influences migration and invasion. T-cadherin is thought to affect cellular function largely through its signaling and not its adhesion properties because the molecule is anchored into the cell membrane by a glycosylphosphatidylinositol (GPI) moiety. However, detailed knowledge about the consequences of the loss of T-cadherin in melanoma is currently lacking. For this reason, we were interested in assessing which signaling pathways are initiated by T-cadherin. The tumor growth of subcutaneously injected T-cadherin-positive melanoma cells was diminished compared with T-cadherin-negative cells in nude mice. The difference in tumor volume was not due to decreased proliferation but rather due to increased apoptosis. After the expression of T-cadherin was induced, we detected V-AKT murine thymoma viral oncogene homolog (AKT) and FoxO3a hypophosphorylation accompanied by the downregulation of the antiapoptotic molecules BCL-2, BCL-x and Clusterin. Furthermore, we detected a diminished transcriptional activity of CREB and AP-1. We demonstrated that T-cadherin functions as a pro-apoptotic tumor suppressor that antagonizes AKT/CREB/AP-1/FoxO3a signaling, whereas NFκB, TCF/LEF and mTOR are not part of the T-cadherin signaling pathway. Notably, we found that the restoration of T-cadherin in melanoma cells causes sensitization to apoptosis induced by CD95/Fas antibody CH-11.
对信号通路的了解是治疗黑色素瘤的基本要求。目前，激酶是黑色素瘤治疗的核心。根据我们的研究，其他替代分子对黑色素瘤的发展同样重要。在这方面，癌症进展除其他因素外，还由钙黏蛋白介导的黏附改变所驱动。例如，在包括黑色素瘤在内的各种癌症类型中都发现了黏附分子T-钙黏蛋白的表达失调，并且它会影响迁移和侵袭。T-钙黏蛋白被认为主要通过其信号传导而非黏附特性来影响细胞功能，因为该分子通过糖基磷脂酰肌醇（GPI）部分锚定在细胞膜中。然而，目前缺乏关于黑色素瘤中T-钙黏蛋白缺失后果的详细知识。因此，我们有兴趣评估哪些信号通路是由T-钙黏蛋白启动的。与裸鼠体内的T-钙黏蛋白阴性细胞相比，皮下注射的T-钙黏蛋白阳性黑色素瘤细胞的肿瘤生长有所减少。肿瘤体积的差异不是由于增殖减少，而是由于凋亡增加。诱导T-钙黏蛋白表达后，我们检测到V-AKT小鼠胸腺瘤病毒癌基因同源物（AKT）和FoxO3a去磷酸化，同时抗凋亡分子BCL-2、BCL-x和Clusterin下调。此外，我们检测到CREB和AP-1的转录活性降低。我们证明T-钙黏蛋白作为一种促凋亡肿瘤抑制因子，拮抗AKT/CREB/AP-1/FoxO3a信号传导，而NFκB、TCF/LEF和mTOR不是T-钙黏蛋白信号通路的一部分。值得注意的是，我们发现黑色素瘤细胞中T-钙黏蛋白的恢复会导致对CD95/Fas抗体CH-11诱导的凋亡敏感。
