Abstract 4039: Cadmium modulates steatosis, fibrogenesis, and oncogenic signaling in hepatocellular carcinoma cells through activation of Notch/AKT/mTOR pathways

Abstract Cadmium (Cd) is an environmental pollutant that increases hepatotoxicity and the risk of liver diseases. In the current study, we investigated the effect of a physiologically relevant, low concentration of Cd on the regulation of liver cancer cell proliferation, steatosis, and fibrogenic/oncogenic signaling. Exposure of Cd (1 to 10 nM) increased endogenous reactive oxygen species (ROS) production and enhanced cell proliferation in non-tumor derived HepaRG liver cells and in hepatocellular carcinoma (HCC) cell lines. Exposure of Cd increased Jagged1 expression and activated Notch signaling in HepaRG and HCC cell lines. Cd activated AKT/mTOR signaling by increasing phosphorylation of AKT-S473 and mTOR-S-4448 residues. Moreover, a low concentration of Cd also promoted cell steatosis and induced fibrogenic signaling in HCC cells. Similarly chronic exposure of HCC cells to a low concentration of Cd activated Notch and AKT/mTOR signaling. Further RNA seq data revealed that chronic Cd exposure modulate cell steatosis/fibrogenic gene expression that involved in fatty liver disease development. Cd induced the expression of pro-inflammatory cytokines TNFα and its downstream oncogenic protein Tumor Necrosis Factor-alpha (TNF-α)-Induced Protein 8 (TNFAIP8). Collectively our data suggest that a low concentration of Cd modulates cell steatosis and fibrogenic/oncogenic signaling in HCC by activation of Notch/AKT/mTOR pathways. Citation Format: Suryakant Niture, Sashi Gadi, Minghui Lin, Qi Qi, John T. Moore, Deepak Kumar. Cadmium modulates steatosis, fibrogenesis, and oncogenic signaling in hepatocellular carcinoma cells through activation of Notch/AKT/mTOR pathways [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4039.