LiCl induces TNF-α and FasL production, thereby stimulating apoptosis in cancer cells

Rhabdomyosarcomas (RMS) are the most prevalent soft tissue sarcomas affecting children and adolescents. Despite intensive treatment consisting of multimodal chemotherapy and surgery RMS patients diagnosed with metastatic disease expect long term survival rates of only 20%. Often multidrug resistance arises upon initial response emphasizing the need for new therapeutic drugs to improve treatment efficiency. Previously, we demonstrated the efficacy of the FDA approved drug arsenic trioxide (ATO) specifically inhibiting viability and clonal growth as well as inducing cell death in human RMS cell lines of different subtypes. In this study, we combined low dose ATO with lithium chloride (LiCl), which is approved as mood stabilizer for the treatment of bipolar disorder, but also inhibits growth and survival of different cancer cell types in pre-clinical research. Indeed, we could show additive effects of LiCl and ATO on viability reduction, decrease of colony formation as well as cell death induction. In the course of this, LiCl induced inhibitory glycogen synthase kinase-3β (GSK-3β) serine 9 phosphorylation, whereas glioma associated oncogene family 1 (GLI1) protein expression was particularly reduced by combined ATO and LiCl treatment in RD and RH-30 cell lines, showing high rates of apoptotic cell death. These results imply that combination of ATO with LiCl or another drug targeting GSK-3 is a promising strategy to enforce the treatment efficiency in resistant and recurrent RMS.

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“…Inhibition of Hh and GSK-3 pathways reduces proliferation and induces apoptotic cell death of tumor cells in vitro and in vivo [9, 10, 23, 24]. …”

Section: Discussionmentioning

confidence: 99%

Combined application of arsenic trioxide and lithium chloride augments viability reduction and apoptosis induction in human rhabdomyosarcoma cell lines

et al. 2017

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“…Furthermore, lithium has been shown to inhibit cellular proliferation in combination with the regulation of the expression of genes involved not only with the apoptosis signaling pathway [Zhang et al, ] but also with the production of inflammatory cytokines [Matsebatlela et al, ] . In CRC, lithium induced apoptosis through a mechanism that is independent of p53 activity with increased production of TNF‐α and FasL, two death‐receptor ligands that activate the extrinsic apoptosis pathway [Kaufmann et al, ]. Whether this mechanism occurs in our models remains to be elucidated.…”

Section: Discussionmentioning

confidence: 99%

PTEN Overexpression Cooperates With Lithium to Reduce the Malignancy and to Increase Cell Death by Apoptosis via PI3K/Akt Suppression in Colorectal Cancer Cells

et al. 2015

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Lithium is a well-established non-competitive inhibitor of glycogen synthase kinase-3β (GSK-3β), a kinase that is involved in several cellular processes related to cancer progression. GSK-3β is regulated upstream by PI3K/Akt, which is negatively modulated by PTEN. The role that lithium plays in cancer is controversial because lithium can activate or inhibit survival signaling pathways depending on the cell type. In this study, we analyzed the mechanisms by which lithium can modulate events related to colorectal cancer (CRC) progression and evaluated the role that survival signaling pathways such as PI3K/Akt and PTEN play in this context. We show that the administration of lithium decreased the proliferative potential of CRC cells in a GSK-3β-independent manner but induced the accumulation of cells in G2/M phase. Furthermore, high doses of lithium increased apoptosis, which was accompanied by decreased proteins levels of Akt and PTEN. Then, cells that were induced to overexpress PTEN were treated with lithium; we observed that low doses of lithium strongly increased apoptosis. Additionally, PTEN overexpression reduced proliferation, but this effect was minor compared with that in cells treated with lithium alone. Furthermore, we demonstrated that PTEN overexpression and lithium treatment separately reduced cell migration, colony formation, and invasion, and these effects were enhanced when lithium treatment and PTEN overexpression were combined. In conclusion, our findings indicate that PTEN overexpression and lithium treatment cooperate to reduce the malignancy of CRC cells and highlight lithium and PTEN as potential candidates for studies to identify new therapeutic approaches for CRC treatment.

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“…Recently, it has been shown that inhibition of GSK3β promotes apoptosis in glioma cells and PDA cells [49], [50], and sensitizes PANC-1 cells to gemcitabine [51]. In addition, lithium induces apoptosis of a variety of cancer cells [36], [52]. At present, the mechanism of lithium-mediated anti-cancer activity is not clear.…”

Section: Discussionmentioning

confidence: 99%

“…In fact, it has been suggested that lower cancer prevalence observed in mental patients is likely due to benefit from protection of lithium treatment [34]. At the molecular level, lithium has been shown to inhibit the growth and/or tumorigenicity of cancer cells by modulating the biologic activities of many cancer related genes, for example, STAT3 [35], β-catenin/WNT [30], [31], TNF [33] and FASL [36], and P53 [37].…”

Section: Introductionmentioning

confidence: 99%

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

Peng

Mei

et al. 2013

PLoS ONE

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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.

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LiCl induces TNF-α and FasL production, thereby stimulating apoptosis in cancer cells

Cited by 25 publications

References 46 publications

Combined application of arsenic trioxide and lithium chloride augments viability reduction and apoptosis induction in human rhabdomyosarcoma cell lines

Combined application of arsenic trioxide and lithium chloride augments viability reduction and apoptosis induction in human rhabdomyosarcoma cell lines

PTEN Overexpression Cooperates With Lithium to Reduce the Malignancy and to Increase Cell Death by Apoptosis via PI3K/Akt Suppression in Colorectal Cancer Cells

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

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