Autophagy Inhibition by Sustained Overproduction of IL6 Contributes to Arsenic Carcinogenesis

Qi, Yuanlin; Zhang, Mingfang; Li, Hui; Frank, Jacqueline A.; Dai, Lu; Liu, Huijuan; Zhang, Zhuo; Wang, Chi; Chen, Gang

doi:10.1158/0008-5472.can-13-3182

Cited by 68 publications

(65 citation statements)

References 42 publications

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“…Recently, we further uncovered the involvement of an STAT3-mediated autophagy and inflammation responses in this process. 2 Chronic sterile inflammation caused by continuous carcinogen exposure has been linked to various steps of tumorigenesis. A pathogenic effect of pulmonary inflammation has been shown in several murine models of lung cancer.…”

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STAT3in arsenic lung carcinogenicity

Chen¹

2015

OncoImmunology

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We recently found that the chronic sterile inflammation contributes to arsenic lung tumorigenesis which is inhibited by autophagy. STAT3 regulates the interaction between inflammation and autophagy. STAT3 may also play a critical role in mediating the crosstalk between lung epithelial cells and their microenvironment, including immune cells, during arsenic lung carcinogenesis.Arsenic is a carcinogen and chronic arsenic exposure may cause lung cancer. The tumorigenic action of arsenic is complicated and varied among different cell type (e.g. non-immune vs. immune cells) and durations of arsenic exposure. Here, we explore a possible role of STAT3 in mediating intrinsic and extrinsic pathways that contribute to arsenic lung carcinogenicity.In our previous study, we have shown sub-chronic arsenic exposure induced lung epithelial cells transformation which was accompanied with oxidative stress and autophagy activation.1 Our data further indicate that autophagy acts as a cell selfprotective mechanism against oxidativestress-promoted cell transformation. Arsenic exposure causes sustained oxidative stress. But the activation of autophagy, after an initial boost by acute arsenic administration, decreased in response to prolonged arsenic exposure. Forced upregulation of autophagy ameliorates cell transformation. Our interpretation is that with the adequate protection of autophagy, short-term arsenic exposure does not cause cell transformation. Upon prolonged arsenic exposure, however, with decreased protection of autophagy, sustained oxidative stress induces gene mutation/genomic instability and eventually leads to cell transformation. Recently, we further uncovered the involvement of an STAT3-mediated autophagy and inflammation responses in this process. Chronic sterile inflammation caused by continuous carcinogen exposure has been linked to various steps of tumorigenesis. A pathogenic effect of pulmonary inflammation has been shown in several murine models of lung cancer. Over production of specific cytokines and abnormal activation of transcription factors are underlying the oncogenic action of chronic inflammation. Autophagy, on the other hand, has been proposed as a new immunological paradigm acting as a negative mediator of chronic inflammation. Defects in autophagy under the condition of chronic inflammation are generally in favor of oncogenesis since autophagy functions in cellular homeostasis. Failure to remove cellular garbage in autophagy-defective cells/tissues results in cell injury/death which certainly is an inflammatory stimulus and creates a cancer-prone microenvironment. However, previous work only shows an incomplete picture for the interaction between acute inflammation and autophagy. For instance, IL1b from acute inflammation activates autophagy while TH2 cell-associated cytokines, such as IL4 and IL13, inhibit autophagy.3 Conversely, autophagy has been shown to inhibit acute inflammatory response. So far little is known regarding the interaction between chronic inflammation and autophagy as well as h...

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“…2 The level of IL6 is increased upon prolonged arsenic exposure which inhibits autophagy activation and thus enhances arsenic-induced cell transformation. Our in both epithelial and immune cells through autocrine or paracrine mechanisms.…”

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STAT3in arsenic lung carcinogenicity

Chen¹

2015

OncoImmunology

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“…These observations suggest that any pro-inflammatory stimulus or agent that gains entry to the body through different routes could induce the same negative effect on human cognitive functions. In this sense, several reports have shown that acute or chronic exposure to iAs or its methylated metabolites lead to inflammatory responses activation in diverse cell types [15][16][17]; therefore, exposure to arsenicals may increase the risk for cognitive impairment through the induction of a sustained inflammatory response.…”

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confidence: 99%

Cortical Astrocytes Acutely Exposed to the Monomethylarsonous Acid (MMAIII) Show Increased Pro-inflammatory Cytokines Gene Expression that is Consistent with APP and BACE-1: Over-expression

et al. 2016

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Long-term exposure to inorganic arsenic (iAs) through drinking water has been associated with cognitive impairment in children and adults; however, the related pathogenic mechanisms have not been completely described. Increased or chronic inflammation in the brain is linked to impaired cognition and neurodegeneration; iAs induces strong inflammatory responses in several cells, but this effect has been poorly evaluated in central nervous system (CNS) cells.Because astrocytes are the most abundant cells in the CNS and play a critical role in brain homeostasis, including regulation of the inflammatory response, any functional impairment in them can be deleterious for the brain. We propose that iAs could induce cognitive impairment through inflammatory response activation in astrocytes. In the present work, rat cortical astrocytes were acutely exposed in vitro to the monomethylated metabolite of iAs (MMA III ), which accumulates in glial cells without compromising cell viability. MMA III LD 50 in astrocytes was 10.52 μM, however, exposure to sub-toxic MMA III concentrations (50 to 1000 nM) significantly increased IL-1β, IL-6, TNF-α, COX-2, and MIF-1 gene expression. These effects were consistent with amyloid precursor protein (APP) and β-secretase (BACE-1) increased gene expression, mainly for those MMA III concentrations that also induced TNF-α over-expression. Other effects of MMA III on cortical astrocytes included increased proliferative and metabolic activity. All tested MMA III concentrations led to an inhibition of intracellular lactate dehydrogenase (LDH) activity. Results suggest that MMA III induces important metabolic and functional changes in astrocytes that may affect brain homeostasis and that inflammation may play a major role in cognitive impairment-related pathogenicity in As-exposed populations.

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“…These are combined with an exaggerated and often inappropriate inflammatory response. For example, the research of several investigators has shown that prenatal arsenic exposure produces altered pro-inflammatory signaling [7,8], including the overproduction of pro-inflammatory cytokines such as interleukin-6 (IL-6) [9]. Inappropriate immune production of inflammatory mediators facilitates the activation of redox pathways [10], which contributes to tissue pathology and potentially to later-life cancer.…”

Section: Arsenicmentioning

confidence: 99%

Effects of Endocrine Disrupters on Immune Function and Inflammation

Dietert¹

2015

Endocrine Disruption and Human Health

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Autophagy Inhibition by Sustained Overproduction of IL6 Contributes to Arsenic Carcinogenesis

Cited by 68 publications

References 42 publications

STAT3in arsenic lung carcinogenicity

STAT3in arsenic lung carcinogenicity

Cortical Astrocytes Acutely Exposed to the Monomethylarsonous Acid (MMAIII) Show Increased Pro-inflammatory Cytokines Gene Expression that is Consistent with APP and BACE-1: Over-expression

Effects of Endocrine Disrupters on Immune Function and Inflammation

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