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Cr(VI) induces cytotoxicity in vitro through activation of ROS-mediated endoplasmic reticulum stress and mitochondrial dysfunction via the PI3K/Akt signaling pathway.
Toxicol In Vitro. 2017 Jun; 41:232-244.TV

Abstract

The occupational and environmental toxicant hexavalent chromium [Cr(VI)] can cause severe damage to the liver; however, the exact mechanisms associated with its toxicity have not been thoroughly demonstrated. In the present study, the underlying mechanisms of Cr(VI)-induced hepatotoxicity were investigated. Our results showed that Cr(VI) inhibited the growth and proliferation of L-02 hepatocytes. Further study revealed that Cr(VI) significantly induced S-phase cell cycle arrest and apoptosis accompanying with the overproduction of reactive oxygen species (ROS). Cr(VI)-induced apoptosis could be prevented by inhibiting ROS with N-acetyl-l-cysteine (NAC). Additionally, our data showed that Cr(VI)-induced endoplasmic reticulum (ER) stress and mitochondrial dysfunction were concentration- and time-dependent. Moreover, inhibition of C/EBA homologous protein (CHOP) expression by siRNA partially prevented Cr(VI)-induced cell apoptosis, mitochondrial dysfunction and ROS generation. We also found that Cr(VI) treatment inhibited the PI3K/Akt pathway in a concentration- and time-dependent manner. After using IGF-1 (50ng/mL), the specific agonist of the PI3K/AKT signaling pathway, the facilitating effects of Cr(VI) were depressed. This finding demonstrated the relationship between the PI3K/Akt pathway, ER stress and mitochondrial dysfunction. Collectively, these findings indicated that Cr(VI) increased ROS production. Increased ROS production may account for inhibition of the PI3K/Akt pathway and lead to ER stress and mitochondrial dysfunction, which consequently induces apoptosis in L-02 hepatocytes. This study provides novel insights into the molecular mechanisms of Cr(VI)-induced cytotoxicity.

Authors+Show Affiliations

Department of Toxicology, Xiangya School of Public Health, Central South University, Changsha 410078, PR China.Department of Toxicology, Xiangya School of Public Health, Central South University, Changsha 410078, PR China.Department of Toxicology, Xiangya School of Public Health, Central South University, Changsha 410078, PR China.Department of Toxicology, Xiangya School of Public Health, Central South University, Changsha 410078, PR China.Department of Toxicology, Xiangya School of Public Health, Central South University, Changsha 410078, PR China.Department of Toxicology, Xiangya School of Public Health, Central South University, Changsha 410078, PR China. Electronic address: zcg54@csu.edu.cn.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

28323103

Citation

Zhang, Yujing, et al. "Cr(VI) Induces Cytotoxicity in Vitro Through Activation of ROS-mediated Endoplasmic Reticulum Stress and Mitochondrial Dysfunction Via the PI3K/Akt Signaling Pathway." Toxicology in Vitro : an International Journal Published in Association With BIBRA, vol. 41, 2017, pp. 232-244.
Zhang Y, Xiao F, Liu X, et al. Cr(VI) induces cytotoxicity in vitro through activation of ROS-mediated endoplasmic reticulum stress and mitochondrial dysfunction via the PI3K/Akt signaling pathway. Toxicol In Vitro. 2017;41:232-244.
Zhang, Y., Xiao, F., Liu, X., Liu, K., Zhou, X., & Zhong, C. (2017). Cr(VI) induces cytotoxicity in vitro through activation of ROS-mediated endoplasmic reticulum stress and mitochondrial dysfunction via the PI3K/Akt signaling pathway. Toxicology in Vitro : an International Journal Published in Association With BIBRA, 41, 232-244. https://doi.org/10.1016/j.tiv.2017.03.003
Zhang Y, et al. Cr(VI) Induces Cytotoxicity in Vitro Through Activation of ROS-mediated Endoplasmic Reticulum Stress and Mitochondrial Dysfunction Via the PI3K/Akt Signaling Pathway. Toxicol In Vitro. 2017;41:232-244. PubMed PMID: 28323103.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Cr(VI) induces cytotoxicity in vitro through activation of ROS-mediated endoplasmic reticulum stress and mitochondrial dysfunction via the PI3K/Akt signaling pathway. AU - Zhang,Yujing, AU - Xiao,Fang, AU - Liu,Xinmin, AU - Liu,Kaihua, AU - Zhou,Xiaoxin, AU - Zhong,Caigao, Y1 - 2017/03/18/ PY - 2016/10/17/received PY - 2017/02/27/revised PY - 2017/03/14/accepted PY - 2017/3/23/pubmed PY - 2018/3/23/medline PY - 2017/3/22/entrez KW - Apoptosis KW - Cr(VI) KW - ER stress KW - Mitochondrial dysfunction KW - PI3K/Akt KW - ROS SP - 232 EP - 244 JF - Toxicology in vitro : an international journal published in association with BIBRA JO - Toxicol In Vitro VL - 41 N2 - The occupational and environmental toxicant hexavalent chromium [Cr(VI)] can cause severe damage to the liver; however, the exact mechanisms associated with its toxicity have not been thoroughly demonstrated. In the present study, the underlying mechanisms of Cr(VI)-induced hepatotoxicity were investigated. Our results showed that Cr(VI) inhibited the growth and proliferation of L-02 hepatocytes. Further study revealed that Cr(VI) significantly induced S-phase cell cycle arrest and apoptosis accompanying with the overproduction of reactive oxygen species (ROS). Cr(VI)-induced apoptosis could be prevented by inhibiting ROS with N-acetyl-l-cysteine (NAC). Additionally, our data showed that Cr(VI)-induced endoplasmic reticulum (ER) stress and mitochondrial dysfunction were concentration- and time-dependent. Moreover, inhibition of C/EBA homologous protein (CHOP) expression by siRNA partially prevented Cr(VI)-induced cell apoptosis, mitochondrial dysfunction and ROS generation. We also found that Cr(VI) treatment inhibited the PI3K/Akt pathway in a concentration- and time-dependent manner. After using IGF-1 (50ng/mL), the specific agonist of the PI3K/AKT signaling pathway, the facilitating effects of Cr(VI) were depressed. This finding demonstrated the relationship between the PI3K/Akt pathway, ER stress and mitochondrial dysfunction. Collectively, these findings indicated that Cr(VI) increased ROS production. Increased ROS production may account for inhibition of the PI3K/Akt pathway and lead to ER stress and mitochondrial dysfunction, which consequently induces apoptosis in L-02 hepatocytes. This study provides novel insights into the molecular mechanisms of Cr(VI)-induced cytotoxicity. SN - 1879-3177 UR - https://www.unboundmedicine.com/medline/citation/28323103/Cr_VI__induces_cytotoxicity_in_vitro_through_activation_of_ROS_mediated_endoplasmic_reticulum_stress_and_mitochondrial_dysfunction_via_the_PI3K/Akt_signaling_pathway_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0887-2333(17)30067-X DB - PRIME DP - Unbound Medicine ER -