Department of Endocrinology, Dr. ALM Post Graduate Institute of Basic Medical Sciences, University of Madras, Taramani Campus, Chennai, 600 113, India.
Biol Trace Elem Res. 2012 Dec;150(1-3):477-86. doi: 10.1007/s12011-012-9510-x. Epub 2012 Oct 7.
Lithium, the first element of Group I in the periodic system, is used to treat bipolar psychiatric disorders. Lithium chloride (LiCl) is a selective inhibitor of glycogen synthase kinase-3β (GSK-3β), a serine/threonine kinase that regulates many cellular processes, in addition to its role in the regulation of glycogen synthase. GSK-3β is emerged as a promising drug target for various neurological diseases, type-2 diabetes, cancer, and inflammation. Several works have demonstrated that lithium can either inhibit or stimulate growth of normal and cancer cells. Hence, the present study is focused to analyze the underlying mechanisms that dictate the biphasic oncogenic properties of LiCl. In the current study, we have investigated the dose-dependent effects of LiCl on human breast cancer cells (MCF-7) by assessing the consequences on cytotoxicity and protein expressions of signaling molecules crucial for the maintenance of cell survival. The results showed breast cancer cells respond in a diverse manner to LiCl, i.e., at lower concentrations (1, 5, and 10 mM), LiCl induces cell survival by inhibiting apoptosis through regulation of GSK-3β, caspase-2, Bax, and cleaved caspase-7 and by activating anti-apoptotic proteins (Akt, β-catenin, Bcl-2, and cyclin D1). In contrast, at high concentrations (50 and 100 mM), it induces apoptosis by reversing these effects. Moreover, LiCl also alters the sodium and potassium levels thereby altering the membrane potential of MCF-7 cells. Thus it is inferred that LiCl exerts a dose-dependent biphasic effect on breast cancer cells (MCF-7) by altering the apoptotic/anti-apoptotic balance.
锂，元素周期表第一主族的第一个元素，被用于治疗双相情感障碍等精神疾病。氯化锂（LiCl）是糖原合酶激酶-3β（GSK-3β）的选择性抑制剂，GSK-3β 是一种丝氨酸/苏氨酸激酶，除了在调节糖原合酶方面的作用外，还调节许多细胞过程。GSK-3β 已成为各种神经退行性疾病、2 型糖尿病、癌症和炎症的有前途的药物靶点。有几项研究表明，锂既能抑制也能刺激正常和癌细胞的生长。因此，本研究旨在分析决定 LiCl 双向致癌特性的潜在机制。在本研究中，我们通过评估对细胞存活至关重要的信号分子的细胞毒性和蛋白表达的后果，研究了 LiCl 对人乳腺癌细胞（MCF-7）的剂量依赖性影响。结果表明，乳腺癌细胞对 LiCl 的反应方式不同，即在较低浓度（1、5 和 10mM）下，LiCl 通过调节 GSK-3β、半胱天冬酶-2、Bax 和裂解的半胱天冬酶-7 抑制细胞凋亡，激活抗凋亡蛋白（Akt、β-连环蛋白、Bcl-2 和细胞周期蛋白 D1）诱导细胞存活。相反，在较高浓度（50 和 100mM）下，它通过逆转这些作用诱导细胞凋亡。此外，LiCl 还改变了钠和钾的水平，从而改变了 MCF-7 细胞的膜电位。因此可以推断，LiCl 通过改变细胞凋亡/抗凋亡平衡对乳腺癌细胞（MCF-7）产生剂量依赖性的双向作用。
