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Activation of ER Stress-Dependent miR-216b Has a Critical Role in Salvia miltiorrhiza Ethanol-Extract-Induced Apoptosis in U266 and U937 Cells

1,†, 2,†, 1,† and 1,*
1
Department of Pathology, College of Korean Medicine, Graduate School, Kyung Hee University, 1 Hoegi-dong, Dongdaemun-gu, Seoul 130-701, Korea
2
Department of Science in Korean Medicine, College of Korean Medicine, Graduate School, Kyung Hee University, 1 Hoegi-dong, Dongdaemun-gu, Seoul 130-701, Korea
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Int. J. Mol. Sci. 2018, 19(4), 1240; https://doi.org/10.3390/ijms19041240
Received: 27 February 2018 / Revised: 3 April 2018 / Accepted: 17 April 2018 / Published: 19 April 2018
(This article belongs to the Special Issue Traditional Medicine – Unraveling Its Molecular Mechanism)
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Abstract

Although Salvia miltiorrhiza has been reported to have anti-cancer mechanisms, such as caspase activation, cell cycle arrest, an anti-angiogenesis effect, and Bcl-2 family regulation, its underlying mechanism of endoplasmic reticulum (ER) stress-mediated apoptosis has never been demonstrated. Thus, in this current study, ER stress-related apoptosis via miR-216b of the ethanol extract of Salvia miltiorrhiza (SM) is elucidated for the first time. SM treatment inhibited the viability of U266 and U937 cells in a concentration-dependent manner. However, SM-exposed Raw264.7 cells were intact compared to U266 or U937 cells. Treatment with SM significantly elevated the generation of reactive oxygen species (ROS). The anti-proliferative effect of SM was reversed by pretreatment with the ROS scavenger, N-acetyl-l-cysteine (NAC), compared to cells treated only with SM. Also, SM treatment increased the ER stress by elevation of phosphorylated activating transcription factor 4 (p-ATF4), phosphorylated eukaryotic Initiation Factor 2 (p-eIF2), and phosphorylated protein kinase RNA-like endoplasmic reticulum kinase (p-PERK) expression. Caspase-3 and Poly (ADP-ribose) polymerase (PARP) were cleaved and CCAAT-enhancer-binding protein homologous protein (CHOP) was activated by SM treatment. PARP cleavage and CHOP activation were attenuated by NAC pretreatment. Furthermore, SM increased the tumor suppressor, miR-216b, and suppressed its target, c-Jun. miR-216b inhibitor attenuated the apoptotic effect of SM. Taken together, SM treatment induced apoptosis through regulation of miR-216b and ROS/ER stress pathways. SM could be a potential drug for treatment of multiple myeloma and myeloid leukemia. View Full-Text
Keywords: Salvia miltiorrhiza; oxidative stress; endoplasmic reticulum stress; C/EBP homologous protein; reactive oxygen species; miR-216b; c-Jun Salvia miltiorrhiza; oxidative stress; endoplasmic reticulum stress; C/EBP homologous protein; reactive oxygen species; miR-216b; c-Jun
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Kim, C.; Song, H.-S.; Park, H.; Kim, B. Activation of ER Stress-Dependent miR-216b Has a Critical Role in Salvia miltiorrhiza Ethanol-Extract-Induced Apoptosis in U266 and U937 Cells. Int. J. Mol. Sci. 2018, 19, 1240.

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