The effect of GSK-3β in arsenic-induced apoptosis of malignant tumor cells: a systematic review and meta-analysis

Abstract

Purpose

Arsenic has been reported to induce apoptosis in malignant tumor cells. Therefore, it has been investigated as a chemotherapy. From a mechanistic standpoint, the mitochondrial apoptosis pathway, mediated by GSK-3β, plays an important role in tumor cell apoptosis. Nonetheless, the regulation of GSK-3β by arsenic remains controversial. The study aimed to clarify the mechanism of GSK-3β in arsenic-induced apoptosis of tumor cells.

Materials and methods

We included 19 articles, which conducts the role of GSK-3β in the process of arsenic-induced tumor cell apoptosis by the meta-analysis.

Results

Compared with that of control group, the expression of GSK-3β (SMD= −0.92, 95% CI (−1.78, −0.06)), p-Akt (SMD= −5.46,95% CI (−8.67, −2.24)) were increased in the arsenic intervention group. Meanwhile, the combined treatment of arsenic and Akt agonists can inhibit p-GSK-3β. Using the dose and time subgroup analysis, it was shown that the low-dose (<5 μmol/L) and sub-chronic (>24 h) arsenic exposure could inhibit the expression of p-Akt (P < 0.05). In the subgroup analysis of GSK-3β sites, arsenic could inhibit p-Akt and GSK-3β (Ser9) (SMD = −0.95, 95% CI (−1.56, −0.33)). There was a positive dose-response relationship between arsenic and p-GSK-3β when the dose of arsenic was less than 8 μmol/L. The expression of Mcl-1 and pro-caspase-3 were decreased, while the loss of mitochondrial membrane potential and cleaved-caspase-3 increased significantly when arsenic stimulated GSK-3β (Ser9) (P < 0.05).

Conclusion

The study revealed that arsenic could induce tumor cell apoptosis, by inhibiting p-Akt/GSK-3β, and triggering the Mcl-1-dependent mitochondrial apoptosis pathway.

Keywords:

• Arsenic
• PI3K/Akt
• GSK-3β
• mitochondria
• apoptosis

Acknowledgments

First of all, I would like to express my gratitude to Shugang Li-PhD for his instructive advice and useful suggestions on my thesis. Meanwhile, I am also very grateful to the teacher for giving me help in translation research. Finally, I am indebted to my friends and parents for their support and encouragement.

Author contributions

Xin Gao contributed significantly to analysis and manuscript preparation, extract data from the literature, performed the data analyses, and wrote the manuscript; Bin Deng and Shanshan Ran contributed to the conception of the study; Shugang Li helped perform the analysis with constructive discussions.

Consent for publication

This paper is approved by all authors for publication.

Disclosure statement

The authors declare no conflicts of interest.

Data availability statement

The datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request.

In this study, the datasets came from PubMed, Web of Science, Cochrane Library, Excerpta Medica database (EMBASE), China National Knowledge Infrastructure (CNKI), Wan Fang Data databases, Wiper databases, and China Biology Medicine disk (CBM disk).

1) PubMed (https://pubmed.ncbi.nlm.nih.gov/), 2) EMBASE (https://www.embase.com/), 3) Web of Science (http://isiknowledge.com/wos), 4) Cochrane Library (https://www.cochranelibrary.com/ library), 5) CNKI (https://www.cnki.net/), 6) Wan Fang Data databases (http://www.wanfangdata.com.cn/index.html), 7) Wiper databases (http://www.cqvip.com), 8) CBM disk (http://www.sinomed.ac.cn/)

Additional information

Funding

This work was supported by the National Natural Science Foundation of China (No.81760584).