Lithium Inhibits Tumorigenic Potential of PDA Cells through Targeting Hedgehog-GLI Signaling Pathway

Abstract

Hedgehog signaling pathway plays a critical role in the initiation and development of pancreatic ductal adenocarcinoma (PDA) and represents an attractive target for PDA treatment. Lithium, a clinical mood stabilizer for mental disorders, potently inhibits the activity of glycogen synthase kinase 3β (GSK3β) that promotes the ubiquitin-dependent proteasome degradation of GLI1, an important downstream component of hedgehog signaling. Herein, we report that lithium inhibits cell proliferation, blocks G1/S cell-cycle progression, induces cell apoptosis and suppresses tumorigenic potential of PDA cells through down-regulation of the expression and activity of GLI1. Moreover, lithium synergistically enhances the anti-cancer effect of gemcitabine. These findings further our knowledge of mechanisms of action for lithium and provide a potentially new therapeutic strategy for PDA through targeting GLI1.

Lithium in Kidney Diseases

“…Moreover, an interesting finding of this study is that in cultured human colon cancer cells, lithium suppressed cell growth and sensitized the cells to cisplatin-induced apoptosis. 10 This observation, in agreement with recent findings in endometrial cancer and pancreatic ductal adenocarcinoma, 13,14 suggests that lithium may reduce the adverse effects of cisplatin in kidneys and enhance the anticancer efficacy during chemotherapy, an inference that requires further in vivo work using tumor-bearing animal models to establish. 15 The study by de Groot et al examined the effects of longterm (up to 13 days) lithium use on renal principal cells and its contribution to NDI, 11 an important renal adverse effect of lithium that is characterized by polyuria and polydipsia due to renal resistance to arginine vasopressin (AVP) and consequent failure of urine concentration.…”

A Metabolic Inhibitory Cocktail for Grave Cancers: Metformin, Pioglitazone and Lithium Combination in Treatment of Pancreatic Cancer and Glioblastoma Multiforme

“…An enhancement of PARP cleavage was shown following treatment with both agents (Deming et al 2010). Hedgehog signaling cascade exerts a prominent role in the initiation and promotion of pancreatic ductal adenocarcinoma (PDA), and thus, it is a logical target for PDA treatment (Peng et al 2013). Lithium blocked cell proliferation, G1/S cell cycle progression, triggered apoptosis and reduced tumorigenicity of PDA cells through decreasing the expression and activity of glioma associated oncogene-1 (GLI1; Gli proteins are the mediators of hedgehog signal and regulate cell differentiation and embryonic development).…”

“…Lithium blocked cell proliferation, G1/S cell cycle progression, triggered apoptosis and reduced tumorigenicity of PDA cells through decreasing the expression and activity of glioma associated oncogene-1 (GLI1; Gli proteins are the mediators of hedgehog signal and regulate cell differentiation and embryonic development). Moreover, lithium increased the anti-tumoral efficacy of gemcitabine (Peng et al 2013). …”

Lithium chloride has a biphasic effect on prostate cancer stem cells and a proportional effect on midkine levels

“…It has cancerogenic and anti-cancerogenic properties, meaning that it can inhibit or stimulate the growth of normal and cancer cells [i.e., it has a biphasic effect). LiCl acts through inhibition of the glycogen synthase kinase-3β (GSK-3β) pathway (an agonist known to activate the Wnt/β-catenin signaling], the phosphoinositide signaling pathway and adenylate cyclase (15)(16)(17)(18)(19). Cancer and/or the cancer treatment itself may lead to psychiatric disorders causing a reduction in life quality and a desire to overcome the illness (20).…”