Arctigenin alleviates ER stress via activating AMPK

Abstract

Aim: To investigate the protective effects of arctigenin (ATG), a phenylpropanoid dibenzylbutyrolactone lignan from Arctium lappa L (Compositae), against ER stress in vitro and the underlying mechanisms. Methods: A cell-based screening assay for ER stress regulators was established. Cell viability was measured using MTT assay. PCR and Western blotting were used to analyze gene and protein expression. Silencing of the CaMKKβ, LKB1, and AMPKα1 genes was achieved by RNA interference (RNAi). An ATP bioluminescent assay kit was employed to measure the intracellular ATP levels. Results: ATG (2.5, 5, and 10 µmol/L) inhibited cell death and unfolded protein response (UPR) in a concentration-dependent manner in cells treated with the ER stress inducer brefeldin A (100 nmol/L). ATG (1, 5, and 10 µmol/L) significantly attenuated protein synthesis in cells through inhibiting mTOR-p70S6K signaling and eEF2 activity, which were partially reversed by silencing AMPKα1 with RNAi. ATG (1-50 µmol/L) reduced intracellular ATP level and activated AMPK through inhibiting complex I-mediated respiration. Pretreatment of cells with the AMPK inhibitor compound C (25 µmol/L) rescued the inhibitory effects of ATG on ER stress. Furthermore, ATG (2.5 and 5 µmol/L) efficiently activated AMPK and reduced the ER stress and cell death induced by palmitate (2 mmol/L) in INS-1 β cells. Conclusion: ATG is an effective ER stress alleviator, which protects cells against ER stress through activating AMPK, thus attenuating protein translation and reducing ER load.

Transcriptional cross talk between orphan nuclear receptor ERR and transmembrane transcription factor ATF6 coordinates endoplasmic reticulum stress response

“…To investigate whether there was any connection between ER stress and ERRγ, AML12 (Mouse hepatoma cell line) cells were treated with known ER stress inducers, Tm, Thapsigargin (45) and Brefeldin A (52). A significant increase in the ERRγ mRNA level was observed by qRT-PCR, though there was no significant increase in ERRα and ERRβ mRNA level (Figure 1A).…”

C1q/TNF-Related Protein 9 (CTRP9) attenuates hepatic steatosis via the autophagy-mediated inhibition of endoplasmic reticulum stress

“…AMPK activation has been reported to attenuate ER stress in various cell types (Gu et al, 2012, Salvado et al, 2013, Wang et al, 2011. Autophagy helps the cell to adapt to stress through clearance of misfolded proteins and damaged organelles (Ogata et al, 2006).…”

Arctigenin inhibits the activation of the mTOR pathway, resulting in autophagic cell death and decreased ER expression in ER-positive human breast cancer cells

“…However, it has also been reported that cells undergo autophagy-induced cell death, if the stress is beyond their comprehension. Previous studies have indicated that arctigenin induces autophagy, which can lead to the death of several cell lines (11,20,(29)(30)(31). Therefore, in this study, to examine the autophagic activity of MCF-7 cells in response to arctigenin treatment, we analyzed the conversion of LC3 (LC3-I) into LC3-II.…”