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MiR-657/ATF2 Signaling Pathway Has a Critical Role in Spatholobus suberectus Dunn Extract-Induced Apoptosis in U266 and U937 Cells

1
College of Korean Medicine, Graduate School, Kyung Hee University, Seoul 130-701, Korea
2
College of Korean Medicine, Kyung Hee University, Seoul 130-701, Korea
3
Department of Science in Korean Medicine, College of Korean Medicine, Graduate School, Kyung Hee University, Seoul 130-701, Korea
*
Author to whom correspondence should be addressed.
These authors equally contributed to this work.
Cancers 2019, 11(2), 150; https://doi.org/10.3390/cancers11020150
Received: 16 January 2019 / Accepted: 23 January 2019 / Published: 28 January 2019
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Abstract

Though Spatholobus suberectus Dunn (SSD) has been reported to have anti-virus, anti-osteoclastogenesis, and anti-inflammation activities, its underlying anti-cancer mechanism has never been elucidated in association with the role of miR-657 in endoplasmic reticulum (ER) stress-related apoptosis to date. SSD treatment exerted cytotoxicity in U266 and U937 cells in a dose-dependent manner. Also, apoptosis-related proteins such as PARP, procaspase-3, and Bax were regulated by SSD treatment. Furthermore, Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay revealed that a number of apoptotic bodies were increased by SSD. Interestingly, the ER stress-related proteins such as p-ATF2 and CHOP were elevated by SSD. Interestingly, reactive oxygen species (ROS) generation and cytotoxicity by SSD treatment were significantly reduced by N-Acetyl-L-cysteine (NAC). Among the microRNAs (miRNAs) regulated by SSD treatment, miR-657 was most significantly reduced by SSD treatment. However, an miR-657 mimic reversed SSD-induced apoptosis by the attenuation of the expression of p-ATF2, CHOP, and PARP cleavage. Overall, these findings provide scientific evidence that miR657 is an onco-miRNA targeting the ER stress signal pathway and SSD induces apoptosis via the inhibition of miR-657, ROS, and the activation of p-ATF2 and CHOP as a potent anti-cancer agent for myeloid-originated hematological cancer. View Full-Text
Keywords: Spatholobus suberectus Dunn; multiple myeloma; myeloid leukemia; reactive oxygen species; N-Acetyl-L-cysteine; endoplasmic reticulum stress; activating transcription factor 2; C/EBP homologous protein; apoptosis; miR-657 Spatholobus suberectus Dunn; multiple myeloma; myeloid leukemia; reactive oxygen species; N-Acetyl-L-cysteine; endoplasmic reticulum stress; activating transcription factor 2; C/EBP homologous protein; apoptosis; miR-657
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).
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Lim, H.J.; Park, M.N.; Kim, C.; Kang, B.; Song, H.-S.; Lee, H.; Kim, S.-H.; Shim, B.-S.; Kim, B. MiR-657/ATF2 Signaling Pathway Has a Critical Role in Spatholobus suberectus Dunn Extract-Induced Apoptosis in U266 and U937 Cells. Cancers 2019, 11, 150.

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