Cadmium Toxicity toward Autophagy through ROS-Activated GSK-3β in Mesangial Cells

Wang, Sheng Hao; Shih, Yu‐Lueng; Kuo, Tai Chin; Ko, Wun-Chang; Shih, Chwen Ming

doi:10.1093/toxsci/kfn266

Cited by 116 publications

(71 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Cadmium induces apoptosis or transformation, depending on exposure concentrations and times (20,21). Cadmium also induces autophagy in the mesangial cells (22,23) and in the skin's epidermal cells (24). Interestingly, cadmium-induced apoptosis, autophagy, or transformation is caused by ROS (20,21,24).…”

mentioning

confidence: 99%

Nrf2/p62 Signaling in Apoptosis Resistance and Its Role in Cadmium-induced Carcinogenesis

Son

Pratheeshkumar

Roy

et al. 2014

Journal of Biological Chemistry

View full text Add to dashboard Cite

Background: Cadmium-transformed cells have a property of apoptosis resistance. Results: Cadmium-transformed cells express high antioxidant enzymes and antiapoptotic proteins. Conclusion:The constitutive p62 and Nrf2 expressions of transformed cells result in a decrease in ROS generation, apoptosis resistance, and tumorigenesis. Significance: Constitutive expression of Nrf2/p62 is important in cadmium carcinogenesis and its possible prevention using these proteins.

show abstract

mentioning

confidence: 99%

Nrf2/p62 Signaling in Apoptosis Resistance and Its Role in Cadmium-induced Carcinogenesis

Son

Pratheeshkumar

Roy

et al. 2014

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…However, cadmium toxicity has been linked to the activation of autophagy in human cells on the basis of the tumorigenic and cell death-inducing properties of this metal (68). The molecular mechanism by which Cd 2ϩ activates autophagic programs in human cells is unclear, although it may involve ROS formation (69)(70)(71). Cadmium has also been shown to induce autophagy in sea urchin embryos, but the underlying signaling pathway remains to be identified (72).…”

Section: Discussionmentioning

confidence: 99%

Activation of Autophagy by Metals in Chlamydomonas reinhardtii

et al. 2015

View full text Add to dashboard Cite

Autophagy is an intracellular self-degradation pathway by which eukaryotic cells recycle their own material in response to specific stress conditions. Exposure to high concentrations of metals causes cell damage, although the effect of metal stress on autophagy has not been explored in photosynthetic organisms. In this study, we investigated the effect of metal excess on autophagy in the model unicellular green alga Chlamydomonas reinhardtii. We show in cells treated with nickel an upregulation of ATG8 that is independent of CRR1, a global regulator of copper signaling in Chlamydomonas. A similar effect on ATG8 was observed with copper and cobalt but not with cadmium or mercury ions. Transcriptome sequencing data revealed an increase in the abundance of the protein degradation machinery, including that responsible for autophagy, and a substantial overlap of that increased abundance with the hydrogen peroxide response in cells treated with nickel ions. Thus, our results indicate that metal stress triggers autophagy in Chlamydomonas and suggest that excess nickel may cause oxidative damage, which in turn activates degradative pathways, including autophagy, to clear impaired components and recover cellular homeostasis. Eukaryotic cells are able to degrade and recycle their own material when they are exposed to nutrient starvation or other adverse conditions through a catabolic pathway known as macroautophagy or autophagy. This process is characterized by the formation of double-membrane vesicles termed autophagosomes that engulf and deliver cytosolic components to the vacuole/lysosome for degradation (1-4). The primary function of autophagy is to recycle cytoplasmic material as well as to clear damaged organelles or toxic cellular components generated during stress in order to maintain cellular homeostasis. In higher eukaryotes, autophagy has also been implicated in cell differentiation, development and cell death, and several human pathologies, such as cancer and neurodegenerative diseases (5, 6).Autophagy is mediated by highly conserved autophagy-related (ATG) genes, which have been described in organisms ranging from yeasts to mammals. Some ATG proteins are required for the formation of the autophagosome and constitute the core autophagy machinery (4,7,8). This group of proteins includes the ATG8 and ATG12 ubiquitin-like systems required for vesicle expansion. The ATG8 protein has been widely used to monitor autophagy in many systems (9) because, unlike other ATG proteins, this protein firmly binds to the autophagosome membrane through a covalent bond to phosphatidylethanolamine (PE). Most of the core ATG proteins are conserved in land plants (10-12) and in evolutionarily distant algae, including freshwater species, such as the model green alga Chlamydomonas reinhardtii (herein referred to as Chlamydomonas) (13) and marine species (14). Our current knowledge about autophagy in algae is still limited compared to our knowledge about autophagy in other eukaryotes, but recent studies, mainly performed in Chlamydomon...

show abstract

“…Considering that ROS stress could serve as a potential trigger of autophagy (42), we determined whether MLN4924-induced autophagy in liver cancer cells is also attributed to ROS stress by adding N-acetyl cysteine (NAC), a classical ROS scavenger, to cell culture medium (43). As the result, NAC significantly blocked the conversion of LC3 I to LC3 II induced by MLN4924 in both Huh-7 and Hep G2 cells ( Supplementary Fig.…”

Section: Mln4924-induced Autophagy Is Partially Attributed To Mtor Inmentioning

confidence: 99%

The Nedd8-Activating Enzyme Inhibitor MLN4924 Induces Autophagy and Apoptosis to Suppress Liver Cancer Cell Growth

Luo

Lee³

et al. 2012

Cancer Research

199

204

View full text Add to dashboard Cite

Posttranslational neddylation of cullins in the Cullin-Ring E3 ligase (CRL) complexes is needed for proteolytic degradation of CRL substrates, whose accumulation induces cell-cycle arrest, apoptosis, and senescence. The Nedd8-activating enzyme (NAE) is critical for neddylation of CRL complexes and their growth-promoting function. Recently, the anticancer small molecule MLN4924 currently in phase I trials was determined to be an inhibitor of NAE that blocks cullin neddylation and inactivates CRL, triggering an accumulation of CRL substrates that trigger cell-cycle arrest, apoptosis, and senescence in cancer cells. Here, we report that MLN4924 also triggers autophagy in response to CRL inactivation and that this effect is important for the ability of MLN4924 to suppress the outgrowth of liver cancer cells in vitro and in vivo. MLN4924-induced autophagy was attributed partially to inhibition of mTOR activity, due to accumulation of the mTOR inhibitory protein Deptor, as well as to induction of reactive oxygen species stress. Inhibiting autophagy enhanced MLN4924-induced apoptosis, suggesting that autophagy is a survival signal triggered in response to CRL inactivation. In a xenograft model of human liver cancer, MLN4924 was well-tolerated and displayed a significant antitumor effect characterized by CRL inactivation and induction of autophagy and apoptosis in liver cancer cells. Together, our findings support the clinical investigation of MLN4924 for liver cancer treatment and provide a preclinical proof-of-concept for combination therapy with an autophagy inhibitor to enhance therapeutic efficacy. Cancer Res; 72(13); 3360-71. Ó2012 AACR.

show abstract

Cadmium Toxicity toward Autophagy through ROS-Activated GSK-3β in Mesangial Cells

Cited by 116 publications

References 37 publications

Nrf2/p62 Signaling in Apoptosis Resistance and Its Role in Cadmium-induced Carcinogenesis

Nrf2/p62 Signaling in Apoptosis Resistance and Its Role in Cadmium-induced Carcinogenesis

Activation of Autophagy by Metals in Chlamydomonas reinhardtii

The Nedd8-Activating Enzyme Inhibitor MLN4924 Induces Autophagy and Apoptosis to Suppress Liver Cancer Cell Growth

Contact Info

Product

Resources

About