4.7 Article

Arsenic-induced IGF-1 signaling impairment and neurite shortening: The protective roles of IGF-1 through the PI3K/Akt axis

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ENVIRONMENTAL TOXICOLOGY
卷 -, 期 -, 页码 -

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WILEY
DOI: 10.1002/tox.23995

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arsenic; IGF-1; neurite shortening; neurons; PI3K/Akt

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Arsenic can lead to insulin and IGF-1 resistance in human neuroblastoma cells, disrupting cellular signaling and potentially affecting growth and neurite formation by inhibiting tyrosine kinase activity.
We recently reported that arsenic caused insulin resistance in differentiated human neuroblastoma SH-SY5Y cells. Herein, we further investigated the effects of sodium arsenite on IGF-1 signaling, which shares downstream signaling with insulin. A time-course experiment revealed that sodium arsenite began to decrease IGF-1-stimulated Akt phosphorylation on Day 3 after treatment, indicating that prolonged sodium arsenite treatment disrupted the neuronal IGF-1 response. Additionally, sodium arsenite decreased IGF-1-stimulated tyrosine phosphorylation of the IGF-1 receptor beta (IGF-1R beta) and its downstream target, insulin receptor substrate 1 (IRS1). These results suggested that sodium arsenite impaired the intrinsic tyrosine kinase activity of IGF-1R beta, ultimately resulting in a reduction in tyrosine-phosphorylated IRS1. Sodium arsenite also reduced IGF-1 stimulated tyrosine phosphorylation of insulin receptor beta (IR beta), indicating the potential inhibition of IGF-1R/IR crosstalk by sodium arsenite. Interestingly, sodium arsenite also induced neurite shortening at the same concentrations that caused IGF-1 signaling impairment. A 24-h IGF-1 treatment partially rescued neurite shortening caused by sodium arsenite. Moreover, the reduction in Akt phosphorylation by sodium arsenite was attenuated by IGF-1. Inhibition of PI3K/Akt by LY294002 diminished the protective effects of IGF-1 against sodium arsenite-induced neurite retraction. Together, our findings suggested that sodium arsenite-impaired IGF-1 signaling, leading to neurite shortening through IGF-1/PI3K/Akt.

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