Objective To evaluate systematically various regulating effects of arsenic on the PI3K/AKT signaling pathway, providing a basis for revealing the mechanism of arsenic toxicity.
Methods Two researchers independently evaluated the literature quality of databases, such as the China National Knowledge Infrastructure, Vip, Wanfang, Cochrane, Embase, PubMed and Web of Science. They extracted and cross-checked the data. The included result were meta-analyzed using RevMan 5.3 and Stata 12.0.
Results In vitro experiments, the levels of PI3K and P-AKT in the arsenic intervention group were significantly lower than those in the control group, and the levels of PTEN were significantly higher than those in the control group (Z values were 3.01, 3.15, and 1.97, respectively, P < 0.05). Subgroup analysis found that the PTEN level in the arsenic intervention group was significantly higher than that in the control group, and the levels of PI3K and P-AKT (ser473) were significantly lower than those in the control group (Z values were 2.06, 2.34, and 2.92 respectively, P < 0.05). P-AKT level in the short-term (≤ 24 h) arsenic intervention group was significantly lower than that in the control group (Z=2.79, P < 0.05). Levels of PI3K and P-AKT in the high-concentration (≥ 3 μmol/L) arsenic intervention group were significantly lower than those in the control group (Z values were 2.46 and 3.34, respectively, P < 0.05).The expressions of AKT, P-AKT and P-AKT (ser473) after arsenic combined with PI3K inhibitors significantly decreased than the arsenic intervention group. In vivo experiments, the levels of PI3K and P-AKT in the arsenic intervention group were significantly lower than those in the control group (Z values were 2.40 and 4.25 respectively, P < 0.05). Subgroup analysis showed that the P-AKT level of the arsenic intervention group was significantly lower than that of the control group for a long time (>14 d) (Z=3.01, P < 0.05). Short-term (≤ 14 d) arsenic intervention group of PI3K, P-AKT, AKT levels were significantly lower than those in the control group (Z values were 4.04, 3.67, and 2.17, respectively, P < 0.05). Levels of PI3K and P-AKT in the high-concentration (>3 mg/kg) arsenic intervention group and the levels of AKT and P-AKT in the low-concentration (≤ 3 mg/kg) arsenic intervention group were significantly lower than those in the control group (Z values were 4.04, 3.00, 4.33, and 2.35, respectively, P < 0.05). Analysis of apoptosis indicators showed that after arsenic intervention, the expression levels of apoptosis-related proteins Bax, Cytochrome C, Caspase3, Caspase9, PARP, and apoptosis rate all significantly increased compared with the control group (Z were 3.34, 2.47, 2.05, 2.36, 2.21 and 3.16 respectively, P < 0.05), while Bcl-2 protein expression level significantly decreased (Z=2.05, P < 0.05).
Conclusions Arsenic can induce cell apoptosis by inhibiting PI3K/AKT signaling pathway, and its effect is affected by dose and time of action.
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