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

Authors

Priyanka Sharma, University of New Mexico, Department of Pathology Albuquerque, NM, USA
Trevar S. Caldwell, University of New Mexico, Department of Pathology Albuquerque, NM, USA
Megan N. Rivera, University of New Mexico, Department of Pathology Albuquerque, NM, USA
Rama R. Gullapalli, University of New Mexico, Department of Pathology Albuquerque, NM, USA; University of New Mexico, Department of Chemical and Biological Engineering Albuquerque, NM, USA. Electronic address: rgullapalli@salud.unm.edu

Document Type

Article

Publication Date

9-1-2020

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.

Recommended Citation

Sharma P, Caldwell TS, Rivera MN, Gullapalli RR. Cadmium exposure activates Akt/ERK Signaling and pro-inflammatory COX-2 expression in human gallbladder epithelial cells via a ROS dependent mechanism. Toxicol In Vitro. 2020 Sep;67:104912. doi: 10.1016/j.tiv.2020.104912. Epub 2020 Jun 6. PMID: 32512147; PMCID: PMC7809918.