Hormesis of mercuric chloride-human serum albumin adduct on N9 microglial cells via the ERK/MAPKs and JAK/STAT3 signaling pathways

Tan, Qiaozhu; Liu, Zhitao; Li, Hong; Liu, Yongjun; Xia, Zhijun; Usman, Muhammad; Du, Yuzhi; Bi, Haibo; Wei, Lixin

doi:10.1016/j.tox.2018.07.001

Cited by 13 publications

(8 citation statements)

References 52 publications

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“…The ERK1/2 signaling pathway is a major effector of metal-induced proliferation. This is an already reported mechanism, but we observe it at nanomolar metal concentrations, much lower than usually tested ( 21 , 23 , 24 ). Quantitatively, the effect of metals on the ERK1/2 activation was similar for all compounds examined, but this does not necessarily imply similar activation mechanisms.…”

Section: Discussionsupporting

confidence: 70%

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Thyroid Stem Cells But Not Differentiated Thyrocytes Are Sensitive to Slightly Increased Concentrations of Heavy Metals

et al. 2021

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Thyroid cancer incidence is markedly increased in volcanic areas where residents are biocontaminated by chronic lifelong exposure to slightly increased metals in the environment. Metals can influence the biology of living cells by a variety of mechanisms, depending not only on the dose and length of exposure but also on the type and stage of differentiation of target cells. We explored the effect of five heavy metals (Cu, Hg, Pd, W and Zn) at nanomolar concentrations (the biocontamination level in residents of the volcanic area in Sicily where thyroid cancer is increased) on stimulating the proliferation of undifferentiated (thyrospheres) and differentiated human thyroid cells. Thyrosphere proliferation was significantly increased after exposure to each individual metal and a greater stimulating effect was observed when a mixture of the examined metals was used. No effect was seen in differentiated thyrocytes. For all metals, the dose-response curve followed a biphasic pattern that is typical of hormesis. Thyrosphere growth concerned the size rather than number, except with the metal mixture. An altered morphology was also observed in metal-treated thyrospheres. Metal-induced proliferation was due to activation of the ERK1/2 pathway, as confirmed by growth inhibition when ERK1/2 signaling was blocked. These studies show that stem/precursor thyroid cells are sensitive to small increases in environmental metal concentrations that are harmless for differentiated thyrocytes.

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Section: Discussionsupporting

confidence: 70%

“…To investigate the mechanism involved in the metal-induced growth in human thyrospheres, we measured the extracellular signal-regulated protein kinase phosphorylation (ERK1/2), a pathway that is already reported to be activated by cell exposure to metals ( 17 , 21 – 24 ).…”

Section: Resultsmentioning

confidence: 99%

Thyroid Stem Cells But Not Differentiated Thyrocytes Are Sensitive to Slightly Increased Concentrations of Heavy Metals

et al. 2021

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“…It has been reported that targeting STAT3 affected cell proliferation and migration in cancer cells [ 30 , 31 ], and activation of JAK/STAT3 signaling pathway via enhancing EMT increases tumorigenic and metastatic ability and chemoresistance in cancer cells [ 32 ]. JAK/STAT3 signaling could be activated by cytokines [ 33 ], growth factors [ 34 ], intracellular proteins [ 35 ], including non-receptor kinases [ 36 , 37 ]. In the study, enforced PEAK1 expression promoted JAK1/2 and STAT3 phosphorylation, whereas PEAK1 knockdown has the contrary effect.…”

Section: Discussionmentioning

confidence: 99%

Pseudopodium enriched atypical kinase 1(PEAK1) promotes invasion and of melanoma cells by activating JAK/STAT3 signals

2021

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Pseudopodium enriched atypical kinase 1(PEAK1) is a non-receptor tyrosine kinase, which is enriched in the pseudopodia of migrating cells and plays an important role in regulating cell migration and proliferation. In the study, we investigate the therapeutic effect of PEAK1 on melanoma cells in vitro and in vivo. We used a lentiviral vector to express short hairpin RNAs (Lv-PEAK1 shRNA) for inhibiting PEAK1 expression in the melanoma SKMEL28 cells. A full-length PEAK1 gene was cloned into the pcDNA 3.1 (+) plasmid and used to infect the melanoma SKMEL19 cells. P6 (also known as Pyridines 6, EMD Chemicals), the Pan-JAK inhibitor, was used to inhibit the Janus kinase/signal transducer and activator of transcription 3 (JAK/STAT3) pathway. The cell counting kit-8 (CCK-8), colony formation assay and transwell assay were used to detect cell proliferation, growth and invasion in vitro. The effect of PEAK1 on melanoma progression in vivo was also evaluated. Protein expression of PEAK1, E-cadherin, vimentin and JAK/STAT3 was measured using western blot assay or immunohistochemistry. The results showed that enforced PEAK1 expression facilitated melanoma cell growth, invasion and metastasis via activating JAK/ STAT3 signals, and PEAK1 knockdown inhibited melanoma cell growth, invasion and metastasis via inactivating JAK/STAT3 signals. Further work demonstrated that P6 (500 nM) treatment reversed PEAK1-induced effect in melanoma cells. PEAK1 promotes tumorigenesis and metastasis via activating JAK/STAT3 signals, and PEAK1 knockdown reduced tumorigenesis and metastasis in melanoma via inactivating JAK/STAT3 signals, providing a novel therapeutic strategy for melanoma treatment.

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“…Redox reactions can be modulated by the variable availability of transition metals that serve as donors of electrons. Through these mechanisms, low levels of ROS may stimulate the activation of the ERK/MAPK (mitogen-activated protein kinase) signaling pathway and, as a consequence, increase protein synthesis, cell proliferation and differentiation, and resistance to stress conditions [91,92,101]. A potential alternative mechanism is the binding to and inhibition of protein tyrosine phosphatases by metals [102], indirectly increasing the activity of tyrosine kinases.…”

Section: Hormesis Effectmentioning

confidence: 99%

Increased Thyroid Cancer Incidence in Volcanic Areas: A Role of Increased Heavy Metals in the Environment?

Malandrino

Russo

Gianì

et al. 2020

IJMS

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Thyroid cancer incidence is significantly increased in volcanic areas, where relevant non-anthropogenic pollution with heavy metals is present in the environment. This review will discuss whether chronic lifelong exposure to slightly increased levels of metals can contribute to the increase in thyroid cancer in the residents of a volcanic area. The influence of metals on living cells depends on the physicochemical properties of the metals and their interaction with the target cell metallostasis network, which includes transporters, intracellular binding proteins, and metal-responsive elements. Very little is known about the carcinogenic potential of slightly increased metal levels on the thyroid, which might be more sensitive to mutagenic damage because of its unique biology related to iodine, which is a very reactive and strongly oxidizing agent. Different mechanisms could explain the specific carcinogenic effect of borderline/high environmental levels of metals on the thyroid, including (a) hormesis, the nonlinear response to chemicals causing important biological effects at low concentrations; (b) metal accumulation in the thyroid relative to other tissues; and (c) the specific effects of a mixture of different metals. Recent evidence related to all of these mechanisms is now available, and the data are compatible with a cause–effect relationship between increased metal levels in the environment and an increase in thyroid cancer incidence.

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Hormesis of mercuric chloride-human serum albumin adduct on N9 microglial cells via the ERK/MAPKs and JAK/STAT3 signaling pathways

Cited by 13 publications

References 52 publications

Thyroid Stem Cells But Not Differentiated Thyrocytes Are Sensitive to Slightly Increased Concentrations of Heavy Metals

Thyroid Stem Cells But Not Differentiated Thyrocytes Are Sensitive to Slightly Increased Concentrations of Heavy Metals

Pseudopodium enriched atypical kinase 1(PEAK1) promotes invasion and of melanoma cells by activating JAK/STAT3 signals

Increased Thyroid Cancer Incidence in Volcanic Areas: A Role of Increased Heavy Metals in the Environment?

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