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Cadmium exposure activates Akt/ERK Signaling and pro-inflammatory COX-2 expression in human gallbladder epithelial cells via a ROS dependent mechanism.

ABSTRACT: Gallbladder cancer (GBC) is the commonest biliary tract cancer with an ill-defined etiology. We examined the role of Cd⁺² exposures in a primary human gallbladder (GB) cell line model in this study. Cd⁺² exposures induced decreased cell viability, reactive oxygen species (ROS) generation, altered Akt/ERK signaling pathway activation, PGE₂ and COX-2 expression in a human primary gallbladder epithelial cell model. Pharmacological inhibitors were used to determine the key drivers of elevated COX-2 expression due to Cd⁺² exposure. Our results show Cd⁺² causes a dose-dependent reduction in GB cell viability (EC50 value - 18.6 μM). Dose-dependent activation of phospho-Akt and phospho-ERK signaling pathways via increased phosphoprotein expression was observed due to Cd⁺². Signaling activation of Akt and ERK was prevented by 5 mM N-Acetyl Cysteine (NAC), establishing the role of ROS as a key driver in the activation process. Importantly, we observed Cd⁺² also caused a dose dependent change in the COX-2 and PGE₂ expression levels. PI3K-Akt and NF-kB signaling pathways play a key role in Cd⁺² exposure induced COX-2 activation in the gallbladder epithelial cells. In conclusion, our study measures the toxicological effects of Cd⁺² exposures on human GB epithelial cells for the first time and establishes the role of Cd⁺² as a possible driver of the Akt/ERK pathway overactivity and chronic inflammation in gallbladder carcinogenesis.

SUBMITTER: Sharma P

PROVIDER: S-EPMC7809918 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundAngiogenesis plays an important role in the survival of tissues, as blood vessels provide oxygen and nutrients required by the resident cells. Thus, targeting angiogenesis is a prominent strategy in many different settings, including both tissue engineering and cancer treatment. However, not all of the approaches that modulate angiogenesis lead to successful outcomes. Angiogenesis-based therapies primarily target pro-angiogenic factors such as vascular endothelial growth factor-A (VEGF) or fibroblast growth factor (FGF) in isolation, and there is a limited understanding of how these promoters combine together to stimulate angiogenesis. Targeting one pathway could be insufficient, as alternative pathways may compensate, diminishing the overall effect of the treatment strategy.MethodsTo gain mechanistic insight and identify novel therapeutic strategies, we have developed a detailed mathematical model to quantitatively characterize the crosstalk of FGF and VEGF intracellular signaling. The model focuses on FGF- and VEGF-induced mitogen-activated protein kinase (MAPK) signaling to promote cell proliferation and the phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) pathway, which promotes cell survival and migration. We fit the model to published experimental datasets that measure phosphorylated extracellular regulated kinase (pERK) and Akt (pAkt) upon FGF or VEGF stimulation. We validate the model with separate sets of data.ResultsWe apply the trained and validated mathematical model to characterize the dynamics of pERK and pAkt in response to the mono- and co-stimulation by FGF and VEGF. The model predicts that for certain ranges of ligand concentrations, the maximum pERK level is more responsive to changes in ligand concentration compared to the maximum pAkt level. Also, the combination of FGF and VEGF indicates a greater effect in increasing the maximum pERK compared to the summation of individual effects, which is not seen for maximum pAkt levels. In addition, our model identifies the influential species and kinetic parameters that specifically modulate the pERK and pAkt responses, which represent potential targets for angiogenesis-based therapies.ConclusionsOverall, the model predicts the combination effects of FGF and VEGF stimulation on ERK and Akt quantitatively and provides a framework to mechanistically explain experimental results and guide experimental design. Thus, this model can be utilized to study the effects of pro- and anti-angiogenic therapies that particularly target ERK and/or Akt activation upon stimulation with FGF and VEGF. Video Abstract.

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Cadmium exposure activates Akt/ERK Signaling and pro-inflammatory COX-2 expression in human gallbladder epithelial cells via a ROS dependent mechanism.

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