Caffeine Potentiates Ethanol-Induced Neurotoxicity Through mTOR/p70S6K/4E-BP1 Inhibition in SH-SY5Y Cells

Abstract

Caffeine is a popular psychostimulant, which is frequently consumed with ethanol. However, the effects of caffeine on neuronal cells constantly exposed to ethanol have not been investigated. Apoptosis and oxidative stress occurring in ethanol-induced neurotoxicity were previously associated with decreased phosphorylation of the mTOR/p70S6K/4E-BP1 signaling proteins. Evidence also suggested that caffeine inhibits the mTOR pathway. In this study, human SH-SY5Y neuroblastoma cells were exposed to caffeine after pretreatment for 24 hours with ethanol. Results indicated that both ethanol and caffeine caused neuronal cell death in a dose- and time-dependent manner. Exposure to 20-mM caffeine for 24 hours magnified reduced cell viability and enhanced apoptotic cell death induced by 200 mM of ethanol pretreatment. The phosphorylation of mTOR, p70S6K, and 4E-BP1 markedly decreased in cells exposed to caffeine after ethanol pretreatment, associated with a decrease of the mitochondrial membrane potential (ΔΨm). These findings suggested that caffeine treatment after neuronal cells were exposed to ethanol resulted in marked cell damages, mediated through enhanced inhibition of mTOR/p70S6K/4E-BP1 signaling leading to impaired ΔΨm and, eventually, apoptotic cell death.

Caffeine Release from Magneto-Responsive Hydrogels Controlled by External Magnetic Field and Calcium Ions and Its Effect on the Viability of Neuronal Cells

“…These findings corroborate those from the literature, i.e., at 10 mM CAF, the enzymatic activity of caspase-3 might induce an apoptotic process [ 9 ], whereas in the concentration range between 10 and 100 μM CAF, cell apoptosis was prevented [ 11 ]. Sangaunchom and coworkers observed that 10 mM and 20 mM of CAF reduced the viability of SH-SY5Y to 75% and 34% of the untreated controls, respectively, after 24 h [ 89 ].…”

Insulin-like growth factor-1 inhibits apoptosis of rat gastric smooth muscle cells under high glucose condition via adenosine monophosphate-activated protein kinase (AMPK) pathway

“…mTOR is co-regulated by Akt and AMPK and mTOR activity is indicated by its phosphorylation. A study found that mTOR regulated apoptosis of neuroblastoma cells mainly through regulation of its downstream targets p70S6K and 4E-BP1 [27]. Multiple phosphorylation sites are present on mTOR, Ser 2448 and Ser 2481 are the phosphorylation sites of mTORC1 and mTORC2, respectively [28].…”

Molecular mechanisms of syncytin-1 in tumors and placental development related diseases

“…And the luciferase activity assay showed that caffeine could also induce the activation of HERV-W environmental promoter, improve the transcription level of syncytin-1, thus promoting the proliferation of NB cells [ 100 ]. Several studies suggested that caffeine could play roles in different pathways, such as releasing calcium stored [ 101 ], activating the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) pathway [ 102 ], inhibiting cellular mTOR/P70S6K/4E-BP1 [ 103 ] or inducing vascular endothelial growth factor expression [ 104 ]. Secondly, treatment of the SK-N-DZ cell line with hypoxia-reoxygenation or DNA methylation inhibitor 5-azacytidine could increase the expression of syncytin-1 [ 99 ].…”