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Cadmium modulates steatosis, fibrosis, and oncogenic signaling in liver cancer cells by activating notch and AKT/mTOR pathways.
Niture, Suryakant; Gadi, Sashi; Lin, Minghui; Qi, Qi; Niture, Samiksha S; Moore, John T; Bodnar, Wanda; Fernando, Reshan A; Levine, Keith E; Kumar, Deepak.
Affiliation
  • Niture S; Julius L. Chambers Biomedical Biotechnology Research Institute, North Carolina Central University Durham, North Carolina, USA.
  • Gadi S; NCCU-RTI Center for Applied Research in Environmental Sciences (CARES), RTI International, Durham, North Carolina, USA.
  • Lin M; Julius L. Chambers Biomedical Biotechnology Research Institute, North Carolina Central University Durham, North Carolina, USA.
  • Qi Q; The Fourth People's Hospital of Ningxia Hui Autonomous Region, Yinchuan, China.
  • Niture SS; Julius L. Chambers Biomedical Biotechnology Research Institute, North Carolina Central University Durham, North Carolina, USA.
  • Moore JT; Julius L. Chambers Biomedical Biotechnology Research Institute, North Carolina Central University Durham, North Carolina, USA.
  • Bodnar W; Julius L. Chambers Biomedical Biotechnology Research Institute, North Carolina Central University Durham, North Carolina, USA.
  • Fernando RA; NCCU-RTI Center for Applied Research in Environmental Sciences (CARES), RTI International, Durham, North Carolina, USA.
  • Levine KE; NCCU-RTI Center for Applied Research in Environmental Sciences (CARES), RTI International, Durham, North Carolina, USA.
  • Kumar D; NCCU-RTI Center for Applied Research in Environmental Sciences (CARES), RTI International, Durham, North Carolina, USA.
Environ Toxicol ; 38(4): 783-797, 2023 Mar.
Article in En | MEDLINE | ID: mdl-36602393
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 to low concentrations of Cd increased endogenous reactive oxygen species (ROS) production and enhanced cell proliferation in a human bipotent progenitor cell line HepaRG and hepatocellular carcinoma (HCC) cell lines. Acute exposure of Cd increased Jagged-1 expression and activated Notch signaling in HepaRG and HCC cells HepG2 and SK-Hep1. 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. Chronic exposure to low concentrations of Cd-activated Notch and AKT/mTOR signaling induced the expression of pro-inflammatory cytokines tumor necrosis factor-alpha (TNFα) and its downstream target TNF-α-Induced Protein 8 (TNFAIP8). RNA-Seq data revealed that chronic exposure to low concentrations of Cd modulated the expression of several fatty liver disease-related genes involved in cell steatosis/fibrosis in HepaRG and HepG2 cells. Collectively, our data suggest that low concentrations of Cd modulate steatosis along with fibrogenic and oncogenic signaling in HCC cells by activating Notch and AKT/mTOR pathways.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Carcinoma, Hepatocellular / Liver Neoplasms Limits: Humans Language: En Journal: Environ Toxicol Journal subject: SAUDE AMBIENTAL / TOXICOLOGIA Year: 2023 Document type: Article Affiliation country: United States

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Carcinoma, Hepatocellular / Liver Neoplasms Limits: Humans Language: En Journal: Environ Toxicol Journal subject: SAUDE AMBIENTAL / TOXICOLOGIA Year: 2023 Document type: Article Affiliation country: United States