Unknown

Dataset Information

0

Cadmium results in accumulation of autophagosomes-dependent apoptosis through activating Akt-impaired autophagic flux in neuronal cells.


ABSTRACT: Environmental exposure to cadmium (Cd) links to neurodegenerative disorders. Autophagy plays an important role in controlling cell survival/death. However, how autophagy contributes to Cd's neurotoxicity remains enigmatic. Here, we show that Cd induced significant increases in autophagosomes with a concomitant elevation of LC3-II and p62 in PC12 cells and primary neurons. Using autophagy inhibitor 3-MA, we demonstrated that Cd-increased autophagosomes contributed to neuronal apoptosis. Impairment of Cd on autophagic flux was evidenced by co-localization of mCherry and GFP tandem-tagged LC3 puncta in the cells. This is further supported by the findings that administration of chloroquine (CQ) potentiated the basic and Cd-elevated LC3-II and p62 levels, autophagosome accumulation and cell apoptosis, whereas rapamycin relieved the effects in the cells in response to Cd. Subsequently, we noticed that Cd evoked the phosphorylation of Akt and BECN1. Silencing BECN1 and especially expression of mutant BECN1 (Ser295A) attenuated Cd-increased autophagosomes and cell death. Of note, inhibition of Akt with Akt inhibitor X, or ectopic expression of dominant negative Akt (dn-Akt), in the presence or absence of 3-MA, significantly alleviated Cd-triggered phosphorylation of Akt and BECN1, autophagosomes, and apoptosis. Importantly, we found that Cd activation of Akt functioned in impairing autophagic flux. Collectively, these results indicate that Cd results in accumulation of autophagosomes-dependent apoptosis through activating Akt-impaired autophagic flux in neuronal cells. Our findings underscore that inhibition of Akt to improve autophagic flux is a promising strategy against Cd-induced neurotoxicity and neurodegeneration.

SUBMITTER: Zhang H 

PROVIDER: S-EPMC6378698 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

altmetric image

Publications

Cadmium results in accumulation of autophagosomes-dependent apoptosis through activating Akt-impaired autophagic flux in neuronal cells.

Zhang Hai H   Dong Xiaoqing X   Zhao Rui R   Zhang Ruijie R   Xu Chong C   Wang Xiaoxue X   Liu Chunxiao C   Hu Xiaoyu X   Huang Shile S   Chen Long L  

Cellular signalling 20181219


Environmental exposure to cadmium (Cd) links to neurodegenerative disorders. Autophagy plays an important role in controlling cell survival/death. However, how autophagy contributes to Cd's neurotoxicity remains enigmatic. Here, we show that Cd induced significant increases in autophagosomes with a concomitant elevation of LC3-II and p62 in PC12 cells and primary neurons. Using autophagy inhibitor 3-MA, we demonstrated that Cd-increased autophagosomes contributed to neuronal apoptosis. Impairmen  ...[more]

Similar Datasets

| S-EPMC4527287 | biostudies-literature
| S-EPMC8549811 | biostudies-literature
| S-EPMC8775759 | biostudies-literature
| S-EPMC6100546 | biostudies-literature
| S-EPMC8611986 | biostudies-literature
| S-EPMC5327481 | biostudies-literature
| S-EPMC3855232 | biostudies-literature
| S-EPMC6424961 | biostudies-literature
| S-EPMC6850524 | biostudies-literature
| S-EPMC8128420 | biostudies-literature