Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
, 17 (3), 4422-4432

A Systematic Review and Meta-Analysis of Bidirectional Effect of Arsenic on ERK Signaling Pathway

Affiliations
Review

A Systematic Review and Meta-Analysis of Bidirectional Effect of Arsenic on ERK Signaling Pathway

Dongjie Li et al. Mol Med Rep.

Abstract

Arsenic is a toxic metal, which ultimately leads to cell apoptosis. ERK is considered a key transcriptional regulator of arsenic‑induced apoptosis. Due to a few controversial issues about arsenic‑mediated extracellular signal‑regulated MAP kinases (ERK) signaling, a meta‑analysis was performed. Subgroup analyses demonstrated that high doses (≥2 µmol/l) of arsenic increased the expression of Ras, ERK, ERK1, ERK2, phosphorylated (p)‑ERK, p‑ERK1, and p‑ERK2, while low doses (<2 µmol/l) decreased the expression of Ras, ERK1, p‑ERK, and p‑ERK2 when compared to control groups. Long term exposure (>24 h) to arsenic led to inhibition of expression of ERK1, p‑ERK1, and p‑ERK2, whereas short‑term exposure (≤24 h) triggered the expression of ERK1, ERK2, p‑ERK, p‑ERK1, and p‑ERK2. Furthermore, normal cells exposed to arsenic exhibited higher production levels of Ras and p‑ERK. Conversely, exposure of cancer cells to arsenic showed a lower level of production of Ras and p‑ERK as well as higher level of p‑ERK1 and p‑ERK2 as compared to control group. Short‑term exposure of normal cells to high doses of arsenic may promote ERK signaling pathway. In contrast, long‑term exposure of cancer cells to low doses of arsenic may inhibit ERK signaling pathway. This study may be helpful in providing a theoretical basis for the diverging result of arsenic adverse effects on one hand and therapeutic mechanisms on the other concerning arsenic‑induced apoptosis.

Figures

Figure 1.
Figure 1.
Flow chart of identifying and including studies. ERK, extracellular signal-regulated MAP kinases.
Figure 2.
Figure 2.
Risk of bias graph.
Figure 3.
Figure 3.
Effects of arsenic on apoptosis. SMD, standardized mean difference; caspase-3, cysteinyl aspartate-specific protease-3; Bcl-2, B-cell lymphoma/leukemia-2 protein; Bax, Bcl-associated X protein.
Figure 4.
Figure 4.
Effects of arsenic exposure on ERK. SMD, standardized mean difference; ERK, extracellular signal-regulated MAP kinases; MEK, mitogen-induced extracellular kinase; p-ERK, phosphorylated extracellular signal-regulated kinase; Raf, serine/threonine-specific protein kinases.
Figure 5.
Figure 5.
Subgroup analyses to determine the effects of arsenic on ERK based on source. SMD, standardized mean difference; ERK, extracellular signal-regulated MAP kinases; MEK, mitogen-induced extracellular kinase; p-ERK, phosphorylated extracellular signal-regulated kinase.
Figure 6.
Figure 6.
Subgroup analyses to determine the effects of arsenic on p-ERK1 based on exposure time. Forest plot showing the impact of arsenic treatment on p-ERK1 compared to controls. Total column represents total number of studies performed. SMD, standardized mean difference; IV, independent variable; 95% CI, 95% confidence interval; SD, standard deviation.
Figure 7.
Figure 7.
Subgroup analyses to determine the effects of arsenic on p-ERK2 based on exposure time. Forest plot showing the impact of arsenic treatment on p-ERK2 compared to controls. Total column represents total number of studies performed. SMD, standardized mean difference; IV, independent variable; 95% CI, 95% confidence interval; SD, standard deviation.
Figure 8.
Figure 8.
Subgroup analysis based on dosage of arsenic. SMD, standardized mean difference. ERK, extracellular signal-regulated MAP kinases; MEK, mitogen-induced extracellular kinase; p-ERK, phosphorylated extracellular signal-regulated kinase.
Figure 9.
Figure 9.
Funnel Plot for p-ERK. Blue-dotted line shows overall estimated standard mean difference. Evidence for publication bias was not found (P=0.490). SMD, standard mean difference; SE, standard error; p-ERK, phosphorylated extracellular signal-regulated kinase.
Figure 10.
Figure 10.
Sensitivity analysis for p-ERK. Stable results were observed for all the studies, indicating no individual study influencing the combined results. CI, confidence interval; p-ERK, phosphorylated extracellular signal-regulated kinase.
Figure 11.
Figure 11.
The ERK signaling pathway. (A) shows that high doses of arsenic for a short period of time enhances Ras, Raf, MEK and ERK phosphorylation in normal cells, thereby the activated ERK translocates from cytoplasm into nucleus, increases levels of Bax protein, decreases levels of Bcl-2 protein and cleaves caspase-3, contributing to cell apoptosis. (B) indicates that, in cancer cells, low dose arsenic intervention for long period of time suppresses phosphorylation of Ras, Raf, MEK and ERK, blocking ERK translocation from cytoplasm into nucleus, thereby increases levels of Bax protein, decreases levels of Bcl-2 protein and cleaves caspase-3, contributing to cell apoptosis. ERK, extracellular signal-regulated MAP kinases; MEK, mitogen-induced extracellular kinase; p-ERK, phosphorylated extracellular signal-regulated kinase; Raf, serine/threonine-specific protein kinases; Bcl-2, B-cell lymphoma/leukemia-2 protein; Bax, Bcl-associated X protein; caspase-3, cysteinyl aspartate-specific protease-3; RTKs, receptor tyrosine kinases.
Figure 11.
Figure 11.
The ERK signaling pathway. (A) shows that high doses of arsenic for a short period of time enhances Ras, Raf, MEK and ERK phosphorylation in normal cells, thereby the activated ERK translocates from cytoplasm into nucleus, increases levels of Bax protein, decreases levels of Bcl-2 protein and cleaves caspase-3, contributing to cell apoptosis. (B) indicates that, in cancer cells, low dose arsenic intervention for long period of time suppresses phosphorylation of Ras, Raf, MEK and ERK, blocking ERK translocation from cytoplasm into nucleus, thereby increases levels of Bax protein, decreases levels of Bcl-2 protein and cleaves caspase-3, contributing to cell apoptosis. ERK, extracellular signal-regulated MAP kinases; MEK, mitogen-induced extracellular kinase; p-ERK, phosphorylated extracellular signal-regulated kinase; Raf, serine/threonine-specific protein kinases; Bcl-2, B-cell lymphoma/leukemia-2 protein; Bax, Bcl-associated X protein; caspase-3, cysteinyl aspartate-specific protease-3; RTKs, receptor tyrosine kinases.

Similar articles

See all similar articles

Cited by 1 PubMed Central articles

References

    1. Singh N, Kumar D, Lal K, Raisuddin S, Sahu AP. Adverse health effects due to arsenic exposure: Modification by dietary supplementation of jaggery in mice. Toxicol Appl Pharmacol. 2010;242:247–255. doi: 10.1016/j.taap.2009.10.014. - DOI - PubMed
    1. Yen CC, Ho TJ, Wu CC, Chang CF, Su CC, Chen YW, Jinn TR, Lu TH, Cheng PW, Su YC, Liu SH. Inorganic arsenic causes cell apoptosis in mouse cerebrum through an oxidative stress-regulated signaling pathway. Arch Toxicol. 2011;85:565–575. doi: 10.1007/s00204-011-0709-y. - DOI - PubMed
    1. Eguchi R, Fujimori Y, Takeda H, Tabata C, Ohta T, Kuribayashi K, Fukuoka K, Nakano T. Arsenic trioxide induces apoptosis through JNK and ERK in human mesothelioma cells. J Cell Physiol. 2011;226:762–768. doi: 10.1002/jcp.22397. - DOI - PubMed
    1. Ray A, Chatterjee S, Mukherjee S, Bhattacharya S. Interplay of loss of ERK dependence and amplification of apoptotic signals in arsenic treated rat hepatocytes. Natl Acad Sci Lett. 2013;36:599–602. doi: 10.1007/s40009-013-0175-6. - DOI
    1. Lau AT, Li M, Xie R, He QY, Chiu JF. Opposed arsenite-induced signaling pathways promote cell proliferation or apoptosis in cultured lung cells. Carcinogenesis. 2004;25:21–28. doi: 10.1093/carcin/bgg179. - DOI - PubMed

MeSH terms

Substances

Feedback