Targeting cell migration and the endoplasmic reticulum stress response with calmodulin antagonists: a clinically tested small molecule phenocopy of SEC62 gene silencing in human tumor cells.
Targeting cell migration and the endoplasmic reticulum stress response with calmodulin antagonists: a clinically tested small molecule phenocopy of SEC62 gene silencing in human tumor cells.
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DOI：
10.1186/1471-2407-13-574
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发表时间：
2013-12-05
期刊：
影响因子：
3.8
通讯作者：
Greiner M
中科院分区：
文献类型：
--
作者：
Linxweiler M;Schorr S;Schäuble N;Jung M;Linxweiler J;Langer F;Schäfers HJ;Cavalié A;Zimmermann R;Greiner M
肿瘤细胞受益于其避免细胞凋亡和侵袭其他组织的能力。内质网（ER）膜蛋白Sec62在这些过程中起关键作用。Sec62对于细胞迁移和保护肿瘤细胞免受thapsigargin诱导的内质网应激至关重要，这两者都与细胞质Ca2+有关。在信号素处理后，SEC62沉默导致胞质Ca2+升高和ER Ca2+泄漏增加。Sec62蛋白水平在不同肿瘤中显著升高，包括前列腺癌、肺癌和甲状腺癌。在肺癌中，采用Kaplan-Meier法和log-rank检验分析Sec62蛋白水平对患者生存的影响。为了阐明Sec62潜在的病理生理功能，进行了Ca2+成像技术、实时细胞分析和细胞迁移试验。比较了钙调素拮抗剂三氟拉嗪（TFP）和蛇酚素A对细胞Ca2+稳态、细胞生长和细胞迁移的影响，以及sirna介导的Sec62缺失或Sec62突变体在体外表达的影响。使用Biacore分析，我们检测了Sec62与Sec61复合物的Ca2+敏感相互作用。Sec62的过量产生与患者生存率降低显著相关。因此，Sec62不仅是这类肿瘤的预测标志物，也是一个有趣的治疗靶点。目前的研究表明，Sec62通过直接和Ca2+敏感的相互作用，在内质网的主要Ca2+泄漏通道Sec61中具有调节功能。Sec62中的Ca2+结合基序对其分子功能至关重要。用钙调素拮抗剂处理的细胞通过抑制细胞迁移和使细胞对信号素敏感来模拟Sec62的耗尽。钙调素拮抗剂联合靶向信号素类似物靶向过度产生Sec62的肿瘤可能提供新的个性化治疗选择。
Tumor cells benefit from their ability to avoid apoptosis and invade other tissues. The endoplasmic reticulum (ER) membrane protein Sec62 is a key player in these processes. Sec62 is essential for cell migration and protects tumor cells against thapsigargin-induced ER stress, which are both linked to cytosolic Ca2+. SEC62 silencing leads to elevated cytosolic Ca2+ and increased ER Ca2+ leakage after thapsigargin treatment. Sec62 protein levels are significantly increased in different tumors, including prostate, lung and thyroid cancer. In lung cancer, the influence of Sec62 protein levels on patient survival was analyzed using the Kaplan-Meier method and log-rank test. To elucidate the underlying pathophysiological functions of Sec62, Ca2+ imaging techniques, real-time cell analysis and cell migration assays were performed. The effects of treatment with the calmodulin antagonists, trifluoperazine (TFP) and ophiobolin A, on cellular Ca2+ homeostasis, cell growth and cell migration were compared with the effects of siRNA-mediated Sec62 depletion or the expression of a mutated SEC62 variant in vitro. Using Biacore analysis we examined the Ca2+-sensitive interaction of Sec62 with the Sec61 complex. Sec62 overproduction significantly correlated with reduced patient survival. Therefore, Sec62 is not only a predictive marker for this type of tumor, but also an interesting therapeutic target. The present study suggests a regulatory function for Sec62 in the major Ca2+ leakage channel in the ER, Sec61, by a direct and Ca2+-sensitive interaction. A Ca2+-binding motif in Sec62 is essential for its molecular function. Treatment of cells with calmodulin antagonists mimicked Sec62 depletion by inhibiting cell migration and rendering the cells sensitive to thapsigargin treatment. Targeting tumors that overproduce Sec62 with calmodulin antagonists in combination with targeted thapsigargin analogues may offer novel personalized therapeutic options.
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