Cadmium modulates steatosis, fibrosis, and oncogenic signaling in liver cancer cells by activating notch and 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 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 Cdactivated Notch and AKT/mTOR signaling induced the expression of pro-inflammatory cytokines tumor necrosis factor-alpha (TNFα) and its downstream target TNFα-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.

Cancer Metabolism: The Role of ROS in DNA Damage and Induction of Apoptosis in Cancer Cells

“…Therefore, ROS accumulation in cancer cells is mediated by multiple biological pathways (Figure 1). tocellular carcinoma (HCC) cells [38]. In the skin of pigmented mice, ultraviolet radi amplifies ROS generation, potentially increasing the risk of malignant melanoma [39 Clinically, the use of anticancer drugs can induce ROS accumulation either direct indirectly.…”

“…Research studies have shown that oxidative stress in the ROS-mediated pathway may be a key mechanism for the biological effects of ambient fine particulate matter [ 37 ]. Niture et al found that the use of a low-concentration of Cd (1–10 nM) increases ROS generation, cell proliferation, and cell steatosis while activating fibrogenic/oncogenic signaling in HepaRG and hepatocellular carcinoma (HCC) cells [ 38 ]. In the skin of pigmented mice, ultraviolet radiation amplifies ROS generation, potentially increasing the risk of malignant melanoma [ 39 , 40 ].…”

Autophagy affects hepatic fibrosis progression by regulating macrophage polarization and exosome secretion

“…Recent studies have demonstrated the role of mTOR in regulating exosome release. 28 Another study demonstrated that inhibition of mTOR complex 1 by rapamycin stimulates exosome release, which occurs concurrently with autophagy. mTOR has been confirmed to be involved in the regulation of autophagy process.…”

Association between novel genetic variants of Notch signaling pathway genes and survival of hepatitis B virus‐related hepatocellular carcinoma

“… 16 The high expression of JAG1 in HCC was associated with HCC patients with earlier onset and lower albumin levels, 17 and the expression and activation of Notch1‐4 were positively associated with the invasion, differentiation, and angiogenesis of HCC. 18 , 19 These studies suggest that the Notch signaling pathway may play an important role in HCC.…”