Autophagy Is a Cell Self-Protective Mechanism Against Arsenic-Induced Cell Transformation

Zhang, Tao; Qi, Yuanlin; Liao, Mingjun; Xu, Mei; Bower, Kimberley A.; Frank, Jacqueline A.; Shen, Han‐Ming; Luo, Jia; Shi, Xianglin; Chen, Gang

doi:10.1093/toxsci/kfs240

Cited by 84 publications

(88 citation statements)

References 46 publications

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“…1 Our data further indicate that autophagy acts as a cell selfprotective mechanism against oxidativestress-promoted cell transformation. Arsenic exposure causes sustained oxidative stress.…”

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confidence: 59%

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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confidence: 59%

STAT3in arsenic lung carcinogenicity

Chen¹

2015

OncoImmunology

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“…SAEC and NL20 were obtained directly from the cell banks and passaged in our lab for fewer than 6 months. Sodium arsenite solution was used for arsenic treatment as previously reported (14). For short-term (24 hours) arsenic exposure, cells were grown to 80–90% confluence before being treated with 0.25 μM sodium arsenite.…”

Section: Methodsmentioning

confidence: 99%

“…Cell transformation was determined by anchorage-independent growth in soft agar as described previously (14). Briefly, equal volumes of 1.5% agar (in 1x PBS) and 1x BEGM were mixed at 40°C.…”

Section: Methodsmentioning

confidence: 99%

“…Sub-chronic exposure of human lung epithelial cells (BEAS-2B) to low dose arsenic inducing cell transformation has been used as an in vitro model system by us and many others (12, 13) for mechanistic study of arsenic carcinogenesis. Using this model system we have previously shown sub-chronic arsenic exposure induced BEAS-2B cell transformation accompanied with increased reactive oxygen species (ROS) generation and autophagy activation (14). However, the patterns for ROS and autophagy alteration were different.…”

Section: Introductionmentioning

confidence: 99%

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Autophagy Inhibition by Sustained Overproduction of IL6 Contributes to Arsenic Carcinogenesis

Qi¹,

Zhang

Li³

et al. 2014

Cancer Research

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Chronic inflammation has been implicated as an etiological factor in cancer, whereas autophagy may help preserve cancer cell survival but exert anti-inflammatory effects. How these phenomena interact during carcinogenesis remains unclear. We explored this question in a human bronchial epithelial cell-based model of lung carcinogenesis that is mediated by sub-chronic exposure to arsenic. We found that sustained overexpression of the pro-inflammatory interleukin IL-6 promoted arsenic-induced cell transformation by inhibiting autophagy. Conversely, strategies to enhance autophagy counteracted the effect of IL-6 in the model. These findings were confirmed and extended in a mouse model of arsenic-induced lung cancer. Mechanistic investigations suggested that mTOR inhibition contributed to the activation of autophagy, whereas IL-6 overexpression was sufficient to block autophagy by supporting Beclin-1/Mcl-1 interaction. Overall, our findings argued that chronic inflammatory states driven by IL-6 could antagonize autophagic states that may help preserve cancer cell survival and promote malignant progression, suggesting a need to uncouple inflammation and autophagy controls to enable tumor progression.

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“…As mentioned by Chen and colleagues, autophagy is a protective mechanism against arsenic-induced oxidative stress which causes genome damage and eventually carcinogenesis. 15,16 Autophagy also plays an important role in cellular defense against excessive inflammation, and defects in autophagy under the condition of chronic inflammation contributes to oncogenesis. 17 In the human bronchial epithelial cellular model of carcinogenesis by subchronic exposure to arsenic, Qi and colleagues have demonstrated that sustained overexpression of the pro-inflammatory IL6 promoted arsenicinduced cell transformation by inhibiting autophagy.…”

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confidence: 99%

Autophagy as the effector and player in DNA damage response of cells to genotoxicants

2015

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Autophagy is a highly conserved pathway in eukaryotic cells induced by a variety of stimuli to remove superfluous or damaged organelles or abnormally aggregated proteins to maintain cellular homeostasis.A remarkable progress in our understanding of autophagy has been made in the past decade, not only regarding the molecular mechanism, but also its fundamental roles in the biological effects of various environmental stresses or the development of some human diseases. The genome of eukaryotic cells is constantly threatened by endogenous and exogenous genotoxic factors. Research in recent years has demonstrated that autophagy is not only one of the fundamental effects of genotoxicants but also a critical player in DNA damage response to genotoxic stress. A series of DNA damage response (DDR) proteins including ATM, p53, PARP-1, DNA-PKcs, TIP60, and so on have been demonstrated to play important roles in DNA damage induced autophagy, which functions as a protective measure to promote cell survival. Autophagy was also shown to play roles in the cellular responses to DNA damage, e.g. cell cycle regulation, apoptosis. Although the importance of autophagy in DDR has been recognized, there are still a lot of questions to answer. For example, how does the cell transduce the nuclei DDR signal to the cytosol to initiate autophagy; what is the mechanism of DDR related autophagy determining cell survival or cell death pathway; and what is the mechanism associating the autophagy and carcinogenesis potential of chronic low dose exposure of toxicants? In this review, we provide an overview and discuss the molecular mechanism of DNA damage induced autophagy, and their mutual regulation and its role in cell fate determination in response to genotoxic effects of environmental toxicants.1. Autophagy as a ubiquitous cellular response to environmental alterations and genotoxic stress Autophagy was described in mammalian cells more than 50 years ago as a machinery to deliver the components and organelles of the cell to lysosomes for degradation. 1 As a highly conserved ubiquitous pathway among eukaryotic cells from yeast to human, autophagy can be induced by a variety of stimuli, such as nutrient starvation, 2 growth factor withdrawal, 3 energetic deprivation, 4 oxidative stress, 5 and pathogen infection. 6-8 Many environmental toxicants have already been demonstrated to induce autophagy through the generation of endoplasmic reticulum (ER)-stress, oxidative stress, and DNA damage induction. Depending on the type of toxicant, and the exposure concentration and duration, autophagy induction could act as coordinated signaling for either death or survival determination in the processes of acute toxic response or late effects.A group of environmental metal pollutants, including cadmium, chromium, mercury, iron and arsenic, has been shown to induce autophagy. 9-13 Autophagy has been considered as the initial response of cells to metal toxicants, which may confer protection against cellular damage or act as a potential biomarker of toxic metal...

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Autophagy Is a Cell Self-Protective Mechanism Against Arsenic-Induced Cell Transformation

Cited by 84 publications

References 46 publications

STAT3in arsenic lung carcinogenicity

STAT3in arsenic lung carcinogenicity

Autophagy Inhibition by Sustained Overproduction of IL6 Contributes to Arsenic Carcinogenesis

Autophagy as the effector and player in DNA damage response of cells to genotoxicants

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