Lithium reduces tumorigenic potential in response to EGF signaling in human colorectal cancer cells

Vidal, Flavia Castello Branco; Araújo, Wallace Martins de; Cruz, André L S; Tanaka, M; Viola, João P. B.; Morgado‐Díaz, José Andrés

doi:10.3892/ijo.2011.955

Cited by 21 publications

(15 citation statements)

References 33 publications

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“…In earlier studies, we showed a correlation between increased cell migration and malignant potential in colorectal cancer cells [10], [31], [34]. Here, we showed increased cell migration in HT-29 cells that were treated with EGF (Fig.…”

Section: Discussionsupporting

confidence: 70%

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Claudin-3 Overexpression Increases the Malignant Potential of Colorectal Cancer Cells: Roles of ERK1/2 and PI3K-Akt as Modulators of EGFR signaling

et al. 2013

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The altered expressions of claudin proteins have been reported during the tumorigenesis of colorectal cancer. However, the molecular mechanisms that regulate these events in this cancer type are poorly understood. Here, we report that epidermal growth factor (EGF) increases the expression of claudin-3 in human colorectal adenocarcinoma HT-29 cells. This increase was related to increased cell migration and the formation of anchorage-dependent and anchorage-independent colonies. We further showed that the ERK1/2 and PI3K-Akt pathways were involved in the regulation of these effects because specific pharmacological inhibition blocked these events. Genetic manipulation of claudin-1 and claudin-3 in HT-29 cells showed that the overexpression of claudin-1 resulted in decreased cell migration; however, migration was not altered in cells that overexpressed claudin-3. Furthermore, the overexpression of claudin-3, but not that of claudin-1, increased the tight junction-related paracellular flux of macromolecules. Additionally, an increased formation of anchorage-dependent and anchorage-independent colonies were observed in cells that overexpressed claudin-3, while no such changes were observed when claudin-1 was overexpressed. Finally, claudin-3 silencing alone despite induce increase proliferation, and the formation of anchoragedependent and -independent colonies, it was able to prevent the EGF-induced increased malignant potential. In conclusion, our results show a novel role for claudin-3 overexpression in promoting the malignant potential of colorectal cancer cells, which is potentially regulated by the EGF-activated ERK1/2 and PI3K-Akt pathways.

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Section: Discussionsupporting

confidence: 70%

“…We have shown that increased cell migration is related to mechanisms of tumor progression in cancer cells [10], [31] and that EGF treatment increased the migration of Caco-2 cells [34]. To determine whether EGF altered the migration of HT-29 cells, we performed wound-healing assays after EGF treatment.…”

Section: Resultsmentioning

confidence: 99%

Claudin-3 Overexpression Increases the Malignant Potential of Colorectal Cancer Cells: Roles of ERK1/2 and PI3K-Akt as Modulators of EGFR signaling

et al. 2013

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“…Although lithium is mainly used to treat mental disorders, it targets not only the nerve cells. Several reports have shown that lithium salts are effective for inhibiting glioma cell [29], colorectal cancer cell [30], medulloblastoma cell [31], hepatocellular carcinoma cell [32] and other cancer cells [33]. 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].…”

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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“…. The GSK3 inhibitor lithium chloride (LiCl, Sigma #62476, dissolved in water) was first tested in concentrations over 10 mM according to Vidal et al 67,. but clearly altered cellular growth of the BALB/c cells (data not shown).…”

Section: Methodsmentioning

confidence: 99%

Insulin-IGF signaling affects cell transformation in the BALB/c 3T3 cell model

Poburski

Leovsky

Boerner

et al. 2016

Sci Rep

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The increased cancer mortality of diabetes type 2 patients is most likely an evidence of the tight connection between tumor development and energy metabolism. A major focus of today’s research is still the identification of key proteins of both diseases and the development of corresponding inhibitors. In this study we combined the two-stage BALB/c-3T3 cell transformation assay (BALB-CTA) with the IR/IGF-1R inhibitor OSI-906 (linsitinib) and analyzed alterations in protein activity and energy parameters in non-transformed as well as transformed cells. OSI-906 successfully inhibited the phosphorylation of IR/IGF-1R and decreased cell growth in non-transformed cells. In the BALB-CTA, a permanent treatment with OSI-906 reduced cellular transformation dose-dependently, whereas a temporary treatment gave evidence for a preventive effect in the promotion phase. Furthermore, even though several key proteins were affected, it was possible to show that the phosphorylation of GSK3, Erk 1/2 and the S6 protein are not crucial for the cell foci reducing effect of OSI-906. Taken together, the BALB-CTA confirmed results of OSI-906 from animal studies and enhanced the knowledge of its mode of action. Therefore, the BALB-CTA offers the opportunity to analyze alterations in the transformation process more precisely and will be helpful to identify effective cancer treatments.

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Lithium reduces tumorigenic potential in response to EGF signaling in human colorectal cancer cells

Cited by 21 publications

References 33 publications

Claudin-3 Overexpression Increases the Malignant Potential of Colorectal Cancer Cells: Roles of ERK1/2 and PI3K-Akt as Modulators of EGFR signaling

Claudin-3 Overexpression Increases the Malignant Potential of Colorectal Cancer Cells: Roles of ERK1/2 and PI3K-Akt as Modulators of EGFR signaling

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

Insulin-IGF signaling affects cell transformation in the BALB/c 3T3 cell model

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