Calcineurin signaling as a negative determinant of keratinocyte cancer stem cell potential and carcinogenesis.
Calcineurin signaling as a negative determinant of keratinocyte cancer stem cell potential and carcinogenesis.
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DOI：
10.1158/0008-5472.can-10-3750
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发表时间：
2011-03-15
期刊：
影响因子：
11.2
通讯作者：
Dotto GP
中科院分区：
文献类型：
--
作者：
Dotto GP
钙调磷酸酶是唯一已知的受钙/钙调蛋白控制的丝氨酸/苏氨酸磷酸酶，是免疫系统的关键调节剂。使用钙调神经磷酸酶抑制药物（如环孢素A和FK 506）治疗患者以防止移植排斥反应，会显著增加皮肤鳞状细胞癌（SCC）的风险，SCC是器官移植后死亡的主要原因。最近的证据表明，钙调磷酸酶信号传导的抑制及其对免疫系统的影响，在角质形成细胞中发挥直接的肿瘤促进作用，增强癌症干细胞的潜力。潜在的机制涉及双负调节轴的中断，由此钙调神经磷酸酶/NFAT抑制p53的负调节因子ATF 3的表达。由此产生的角质形成细胞癌细胞衰老的抑制对于用钙调磷酸酶抑制剂治疗的许多患者可能具有临床意义，并且可能与改变的钙/钙调磷酸酶信号传导起作用的其他癌症类型相关。
Calcineurin is the only known serine/threonine phosphatase under calcium/calmodulin control and key regulator of the immune system. Treatment of patients with calcineurin-inhibitory drugs like Cyclosporin A and FK506 to prevent graft rejection increases dramatically the risk of cutaneous squamous cell carcinoma (SCC), which are a major cause of death after organ transplants. Recent evidence indicates that suppression of calcineurin signalling, together with its impact on the immune system, exerts direct tumor promoting effects in keratinocytes, enhancing cancer stem cell potential. The underlying mechanism involves interruption of a double negative regulatory axis, whereby calcineurin/NFAT inhibits expression of ATF3, a negative regulator of p53. The resulting suppression of keratinocyte cancer cell senescence is of likely clinical significance for the many patients under treatment with calcineurin inhibitors, and may be of relevance for other cancer types where altered calcium/calcineurin signalling plays a role.