Pb²⁺ induces gastrin gene expression by extracellular signal‐regulated kinases 1/2 and transcription factor activator protein 1 in human gastric carcinoma cells

Abstract

Divalent lead ions (Pb(2+) ) are toxic environmental pollutants known to cause serious health problems in humans and animals. Absorption of Pb(2+) from air, water, and food takes place in the respiratory and digestive tracts. The ways in which absorbed Pb(2+) affects cell physiology are just beginning to be understood at the molecular level. Here, we used reverse transcription PCR and Western blotting to analyze cultures of human gastric carcinoma cells exposed to 10 μM lead nitrate. We found that Pb(2+) induces gastrin hormone gene transcription and translation in a time-dependent manner. Promoter deletion analysis revealed that activator protein 1 (AP1) was necessary for gastrin gene transcription in cells exposed to Pb(2+) . MitogIen-activated protein kinase (MAPK)/ERK kinase inhibitor PD98059 suppressed the Pb(2+) -induced increase in messenger RNA. Epidermal growth factor receptor (EGFR) inhibitors AG1478 and PD153035 reduced both transcription and phosphorylation by extracellular signal-regulated kinase (ERK1/2). Cells exposed to Pb(2+) also increased production of c-Jun protein, a component of AP1, and over-expression of c-Jun enhanced activation of the gastrin promoter. In sum, the findings suggest the EGFR-ERK1/2-AP1 pathway mediates the effects of Pb(2+) on gastrin gene activity in cell culture.

Advances in Understanding How Heavy Metal Pollution Triggers Gastric Cancer

“…Pb 2+ activates epidermal growth factor receptor (EGFR) and induces phosphorylation of downstream extracellular signal-regulated kinase (ERK)-1/2, thereby activating AP-1. Overexpression of c-Jun increases activation of the gastrin promoter [ 37 ].…”

The Comparison of the Plasma Levels of the Lead Element in Patients with Gastrointestinal Cancers and Healthy Individuals

“…In this study, half of GI cancers were related to the lower gastrointestinal tracts. The plasma concentrations of Pb in patients with cancer were presented in Table 1 Additionally, the toxic levels of Pb for the gastrointestinal tract dysfunction has been defined in a range of 0.41-0.82 μg/ml (Chan et al, 2015). In this study, the concentration of Pb did not reach the above ranges mentioned earlier.…”

“…But, it seems that cancer-prone tissues such as the GI tract have high sensitivity to Pb-induced damage even at lower concentrations. In this context, animal studies demonstrated that exposure to inorganic Pb causes kidney, lung, and brain cancers (Rousseau et al, 2007;Chan et al, 2015;Wynant et al, 2013). Furthermore, the tissue concentration of Pb could be regarded as an issue that needs to be more taken into account.…”

“…There is no cure for individuals intoxicated with Pb (Garcia-Leston et al, 2010;Silbergeld et al , 2000). Although human studies have not definitely confirmed the link between cancer and Pb toxicity, especially GI cancer, but a number of animal studies have suggested that exposure to inorganic Pb increases the risk of kidney, lung, brain, and hematopoietic cancers (Saghiri et al, 2016;Chan et al, 2015). Despite the increasing knowledge about the genotoxicity of Pb, the mechanism underlying this phenomenon is still opaque.…”

Cadmium promotes the proliferation of triple-negative breast cancer cells through EGFR-mediated cell cycle regulation

“…A number of studies report that metals such as chromium, manganese, nickel, arsenic and lead activate Ras/MAPK pathways (Tessier and Pascal, 2006; Andrew et al, 2009; Chan et al, 2015). Cd-induced activation of MAPK and PI3K has also been reported in the ERα-positive cells and this effect is attributed to the xenoestrogenic effect of Cd (Brama et al, 2007; Ponce et al, 2013).…”