Hepatocytes display a compensatory survival response against cadmium toxicity by a mechanism mediated by EGFR and Src

Martínez-Flores, Karina; Marín, Belén; Arroyo, V.; Ortíz, Laura Velasco; Reyes, Alberto; Gómez-Quiroz, Luís Enrique; Rojas, Emilio; Ruiz, Ma Concepción Gutiérrez

doi:10.1016/j.tiv.2013.01.017

Cited by 23 publications

(14 citation statements)

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“…To explore the mechanism, the activities of a few selected signaling factors were examined. Reportedly, Cd activates Akt, ERK, p38, or JNK in different cell types [ 6 – 9 ]. In HepG2 cells, Akt, ERK, p38, and JNK were phosphorylated (activated) within 2 h of Cd treatment ( Fig 3A ).…”

Section: Resultsmentioning

confidence: 99%

“…Cd induces and activates the metal-responsive transcription factor 1 (MTF-1) which regulates the expression of genes involved in metal homeostasis and oxidative stress [ 4 ]. Cd also stimulates the production of proto-oncogenes, such as c-Jun, c-Fos and c-Myc [ 5 ] and activates several signal transduction factors including p38, JNK, ERK, PI3K and Akt [ 6 – 9 ]. Thus, Cd exposure alters significantly the physiological functions of the cells.…”

Section: Introductionmentioning

confidence: 99%

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Cadmium Activates Multiple Signaling Pathways That Coordinately Stimulate Akt Activity to Enhance c-Myc mRNA Stability

2016

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Cadmium is a known environmental carcinogen. Exposure of Cd leads to the activation of several proto-oncogenes in cells. We investigated here the mechanism of c-Myc expression in hepatic cells under Cd treatment. The c-Myc protein and mRNA levels increased in dose- and time-dependent manners in HepG2 cells with Cd treatment. This increase was due to an increase in c-Myc mRNA stability. To explore the mechanism involved in enhancing the mRNA stability, several cellular signaling factors that evoked by Cd treatment were analyzed. PI3K, p38, ERK and JNK were activated by Cd. However, ERK did not participate in the Cd-induced c-Myc expression. Further analysis revealed that mTORC2 was a downstream factor of p38. PI3K, JNK and mTORC2 coordinately activated Akt. Akt was phosphorylated at Thr450 in the untreated cells. Cd treatment led to additional phosphorylation at Thr308 and Ser473. Blocking any of the three signaling factors resulted in the reduction of phosphorylation level at all three Akt sites. The activated Akt phosphorylated Foxo1 and allowed the modified protein to translocate into the cytoplasm. We conclude that Cd-induced accumulation of c-Myc requires the activation of several signaling pathways. The signals act coordinately for Akt activation and drive the Foxo1 from the nucleus to the cytoplasm. Reduction of Foxo1 in the nucleus reduces the transcription of its target genes that may affect c-Myc mRNA stability, resulting in a higher accumulation of the c-Myc proteins.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Cadmium Activates Multiple Signaling Pathways That Coordinately Stimulate Akt Activity to Enhance c-Myc mRNA Stability

2016

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“…Because EGFR has recently been reported to mediate Cd-induced cell proliferation and survival ( Carpenter and Jiang 2013 ; Martinez Flores et al 2013 ), we sought to further determine the contribution of EGFR phosphorylation in p44/42 MAPK activation in the ht-UtLM cells. Cd treatment resulted in phosphorylation of EGFR, which was largely disrupted by the addition of AG1478 (1 μM), a selective EGFR-RTK inhibitor ( Figure 4B,C ).…”

Section: Resultsmentioning

confidence: 99%

Cadmium and Proliferation in Human Uterine Leiomyoma Cells: Evidence of a Role for EGFR/MAPK Pathways but Not Classical Estrogen Receptor Pathways

Gao¹,

Yu²,

Moore³

et al. 2015

Environ Health Perspect

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Background:It has been proposed that cadmium (Cd) is an environmental “metalloestrogen” and that its action is mediated via the estrogen receptor (ER). Cd mimics the effects of estrogen in the rat uterus, and blood Cd concentrations positively correlate with ER levels in uteri of women with fibroids.Objectives:In the present study we explored whether Cd could stimulate proliferation of estrogen-responsive human uterine leiomyoma (ht-UtLM) cells and uterine smooth muscle cells (ht-UtSMCs) through classical interactions with ERα and ERβ, or by nongenomic mechanisms.Methods:We used estrogen response element (ERE) reporters, phosphorylated receptor tyrosine kinase arrays, Western blot analysis, estrogen binding, and cell proliferation assays to evaluate the effects of Cd on ht-UtLM cells and ht-UtSMCs.Results:Cd stimulated growth of both cell types at lower concentrations and inhibited growth at higher concentrations (≥ 50 μM). Cd did not significantly bind to ERα or ERβ, nor did it show transactivation in both cell types transiently transfected with ERE reporter genes. However, in both cells types, Cd (0.1 μM and 10 μM) activated p44/42 MAPK (ERK1/2), and a MAPK inhibitor (PD98059) abrogated Cd-induced cell proliferation. Cd in ht-UtLM cells, but not in ht-UtSMCs, activated the growth factor receptors EGFR, HGFR, and VEGF-R1 upstream of MAPK. Additional studies in ht-UtLM cells showed that AG1478, an EGFR inhibitor, abolished Cd-induced phosphorylation of EGFR and MAPK.Conclusions:Our results show that low concentrations of Cd stimulated cell proliferation in estrogen-responsive uterine cells by nongenomic activation of MAPK, but not through classical ER-mediated pathways.Citation:Gao X, Yu L, Moore AB, Kissling GE, Waalkes MP, Dixon D. 2015. Cadmium and proliferation in human uterine leiomyoma cells: evidence of a role for EGFR/MAPK pathways but not classical estrogen receptor pathways. Environ Health Perspect 123:331–336; http://dx.doi.org/10.1289/ehp.1408234

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“…The generation of ROS during in presense of Cd is associated with the activation of NADPH oxidase system, which is coupled with an increase in phospho-p47 [ 38 ]. NADPH oxidase uses electrons from intracellular NADPH to generate superoxide from molecular oxygen [ 39 ].…”

Section: Discussionmentioning

confidence: 99%

The effects of two common edible herbs, Ipomoea aquatica and Enhydra fluctuans, on cadmium-induced pathophysiology: a focus on oxidative defence and anti-apoptotic mechanism

et al. 2015

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BackgroundIpomoea aquatica (Convolvulaceae) and Enhydra fluctuans (Asteraceae), two aquatic vegetables, are traditionally used against heavy metal toxicity in traditional medicines in India. The present study aimed to explore the protective role of edible (aqueous) extracts of I. aquatica (AEIA) and E. fluctuans (AEEF) against Cd-intoxication.MethodsThe extracts were chemically standardized by spectroscopic and HPLC analysis. The cytoprotective roles of AEIA and AEEF were measured on mouse hepatocytes. The effect on redox status were measured after incubating the hepatocytes with CdCl2 (30 μM) along with AEIA or AEEF (400 μg/ml). The effects on the expressions of apoptotic signal proteins were estimated. The protective roles of AEIA or AEEF were measured by in vivo assay in mice. Haematological, serum biochemical, tissue redox status, Cd bioaccumulation and histological parameters were evaluated to estimate the protective role of AEIA or AEEF (100 mg/kg) against CdCl2 (4 mg/kg) intoxication.ResultsPhytochemical analysis revealed presence of substantial quantities of phenolics, flavonoids, saponins, carbohydrates and ascorbic acid in AEIA or AEEF. CdCl2 treated murine hepatocytes showed a gradual reduction of cell viability in a concentration dependent manner with an IC50 of ~30 μM. CdCl2 treated hepatocytes exhibited significantly enhanced levels (p < 0.01) of ROS production, lipid peroxidation, protein carbonylation and NADPH oxidase with concomitant depletion (p < 0.01) of antioxidant enzymes and GSH. However, AEIA or AEEF treatment along with CdCl2 significantly restored the aforementioned parameters in murine hepatocytes near to normalcy. Besides, AEIA or AEEF significantly counteracted (p < 0.05–0.01) with ROS mediated alteration of transcription levels of signal proteins viz. Bcl-2, BAD, Cyt-C, Caspases, Fas and Bid. In in vivo bioassay, CdCl2 treatment caused significantly high Cd bioaccumulation and oxidative stress in the liver, kidney, heart, brain and testes in mice. In addition, the haematological and serum biochemical parameters were significantly altered in the CdCl2 treated animals. Simultaneous administration of AEIA or AEEF could significantly restore the tested parameters to the near-normal status.ConclusionThe extracts would offer the overall protective effect via counteracting with Cd mediated oxidative stress and/or promoting the elimination of Cd by chelating.

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Hepatocytes display a compensatory survival response against cadmium toxicity by a mechanism mediated by EGFR and Src

Cited by 23 publications

References 38 publications

Cadmium Activates Multiple Signaling Pathways That Coordinately Stimulate Akt Activity to Enhance c-Myc mRNA Stability

Cadmium Activates Multiple Signaling Pathways That Coordinately Stimulate Akt Activity to Enhance c-Myc mRNA Stability

Cadmium and Proliferation in Human Uterine Leiomyoma Cells: Evidence of a Role for EGFR/MAPK Pathways but Not Classical Estrogen Receptor Pathways

The effects of two common edible herbs, Ipomoea aquatica and Enhydra fluctuans, on cadmium-induced pathophysiology: a focus on oxidative defence and anti-apoptotic mechanism

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