Epigallocatechin-3-Gallate (EGCG) Promotes Autophagy-Dependent Survival via Influencing the Balance of mTOR-AMPK Pathways upon Endoplasmic Reticulum Stress

Abstract

The maintenance of cellular homeostasis is largely dependent on the ability of cells to give an adequate response to various internal and external stimuli. We have recently proposed that the life-and-death decision in endoplasmic reticulum (ER) stress response is defined by a crosstalk between autophagy, apoptosis, and mTOR-AMPK pathways, where the transient switch from autophagy-dependent survival to apoptotic cell death is controlled by GADD34. The aim of the present study was to investigate the role of epigallocatechin-3-gallate (EGCG), the major polyphenol of green tea, in promoting autophagy-dependent survival and to verify the key role in connecting GADD34 with mTOR-AMPK pathways upon prolonged ER stress. Our findings, obtained by using HEK293T cells, revealed that EGCG treatment is able to extend cell viability by inducing autophagy. We confirmed that EGCG-induced autophagy is mTOR-dependent and PKA-independent; furthermore, it also required ULK1. We show that pretreatment of cells with EGCG diminishes the negative effect of GADD34 inhibition (by guanabenz or siGADD34 treatment) on autophagy. EGCG was able to delay apoptotic cell death by upregulating autophagy-dependent survival even in the absence of GADD34. Our data suggest a novel role for EGCG in promoting cell survival via shifting the balance of mTOR-AMPK pathways in ER stress.

Fine-tuning of AMPK–ULK1–mTORC1 regulatory triangle is crucial for autophagy oscillation

“…Recently we have also showed that various mTORC1 inhibitors and/or AMPK activators (i.e. resveratrol or EGCG) induced stable autophagy and no oscillation was observed 46,47 . Our computation simulation further confirms that the control network turns on autophagy when mTORC1 down-regulated and AMPK hyper-activated Figure 3.…”

GADD34 is a modulator of autophagy during starvation

“…This role of GADD34 in starvation has some parallelisms to its function in infected cells in response to double-stranded RNAs, where it is needed to allow cytokine production in the face of a general mRNA translation block to prevent viral replication (22). A link between GADD34 and autophagy has been previously reported, but it was related to mTOR inactivation [by starvation (23), by ER stress (24,25), or by the expression of mutant huntingtin proteins (26)], and never associated with either the starvation-induced TFEB transcriptional response or a role in lysosome biogenesis, the two key findings of our work.…”

Protein Kinase C Isozymes and Autophagy during Neurodegenerative Disease Progression

“…Epigallocatechin 3-gallate (EGCG), which is one of the phenolic compounds of green tea, has been reported as a protective agent [168][169][170][171]. EGCG influences autophagy to maintain cell survival under ER stress [172] and decrease the prion accumulation mediated neurodegenerative disease formation by stimulating autophagic flux through SIRT1 activation [173]. EGCG also acts as a neuroprotective agent by inhibiting mitochondrial dysfunction and recovery of impaired autophagy under subarachnoid hemorrhage stroke [174].…”