Wogonoside promotes apoptosis and ER stress in human gastric cancer cells by regulating the IRE1α pathway

Abstract

Gastric cancer is a disease that occurs in the digestive system of humans and remains a problem in the medical field. Wogonoside, a natural flavonoid, has been reported to exert antitumor effects on various types of tumors. However, the effects of wogonoside on gastric cancer remain elusive. The aim of the present study was to detect whether wogonoside treatment could induce apoptosis and ER stress in gastric cancer cells. In the present study, CCK-8 assay was used to detect the cell viability, Annexin V/PI staining was used to detect the cells apoptosis, western blot analysis and real-time PCR analysis was used to detect the endoplasmic reticulum (ER) stress in the AGS and MKN-45 gastric cancer cell lines. Wogonoside treatment reduced the viability of AGS and MKN-45 cells and induced apoptosis. Furthermore, the expression level of caspase-3 and -9 significantly increased following wogonoside treatment compared with that in non-treated cells, and the protein expression levels of proapoptotic Bax and antiapoptotic Bcl-2 increased and decreased, respectively compared with that in the control group. In addition, the phosphorylated protein expression levels of mitogen-activated protein kinase kinase 5 (ASK1) and JNK increased following wogonoside treatment, and the protein expression levels of tumor necrosis factor receptor-associated factor 2 (TRAF2) and serine/threonine-protein kinase/endoribonuclease IRE1 (IRE1α) were also increased following treatment with 50 µM wogonoside for 48 h. Furthermore, the interactions between IRE1α, TRAF2 and ASK1 significantly increased following wogonoside treatment, suggesting that wogonoside induced endoplasmic reticulum (ER) stress in the AGS and MKN-45 cell lines. In addition, small interfering RNA-mediated silencing of IRE1α suppressed the activity of the IRE1α-TRAF2-ASK1 complex and prevented wogonoside-induced cell apoptosis. In conclusion, the results of the present study suggested that wogonoside exhibited antitumor activity by inducing ER stress-associated cell death through the IRE1α-TRAF2-ASK1 pathway.

Inhibitors targeting the autophosphorylation of serine/threonine kinase of Streptococcus suis show potent antimicrobial activity

“…AT9283 and APY29 shared a benzimidazole nucleus. Previous studies have identified AT9283 and APY29 as kinase inhibitors with anticancer and anti-apoptosis activities, respectively (Korennykh et al, 2009;Santo et al, 2011;Qi et al, 2012;Gu et al, 2021). In the current study, AT9283 and APY29 were demonstrated as inhibitors against ssSTK exerting antimicrobial activity against S. suis.…”

New insights into the interplay between autophagy and oxidative and endoplasmic reticulum stress in neuronal cell death and survival

“…The ketamine enhanced autophagy and ERS in vivo and in vitro via restraining IRE1/TRAF2/ ASK1/JNK pathway (Yu et al, 2021). In addition, Wogonoside exhibited antitumor activity by inducing ERS-associated autophagy and cell death by the IRE1α/TRAF2/ASK1 pathway (Gu et al, 2021).…”

Traditional Chinese medicine suppressed cancer progression by targeting endoplasmic reticulum stress responses: A review

“…Thus, the inositol-requiring enzyme-1α (IRE1α)-TRAF2-ASK1 signaling pathway plays a key role in ERS and baicalein-induced apoptosis. [12] 2.2..3. Liver cancer.…”

“…Head and neck cancer 1 Glaucocalyxin A ATF4/ CHOP/CHAC1 pathways [9] 2 Tetrandrine GRP78 and GADD153 [10] Digestive tract tumor 3 Tanshinone IIA BIP and CHOP [11] 4 Wogonoside IRE1α-TRAF2-ASK1 pathways [12] 5 Cyperus amuricus GRP78/BiP; CHOP-URP-PERK/IRE1/ATF6 [13] 6 Muscone PERK/ATF4/DDIT3 pathways [14] 7 Celastrol IRE1α-XBP1s pathways; GRP78/BiP, ATF4 and CHOP [15] 8 Salidroside p-PERK, p-eIF2a, ATF-6 and CHOP [16] 9 TTF1-NPs GRP78, PERK, IRE1α, ATF6 and CHOP; PERK-eIF2α-ATF4 and ATF6 [17,18] 10 Epigallocatechin-3-gallate p-PERK and p-eIF2α [19] 11 Shikonin PERK/elF2α/ATF4/CHOP, and IRE1α/JNK [20] 12 Gambogenic acid IRE1α, BiP, p-eIF2α, and ATF4 [21] 13 A purified resin glycoside fraction from pharbitidis semen ERS-JNK pathways [22] Gynecologic urogenital tumors 14 Saikosaponin-A GPR78 and CHOP [23] 15 Identification of dihydrotanshinone I PERK [24] Non-small cell lung cancer 16 Kushenol Z CHOP [25] 17 Evodiamine IRE1α-TRAF2-ASK1-JNK [26] 18 flavonoid components in Astragali Radix IRE1α-XBP1s [27] Others 19 Shikonin p-eIF2α and CHOP [28] 20 Psoralen CHOP, IREa, XBP-1s, GRP78, PERK and ATF-6 [29] 21 Artesunate ATF4-CHOP-CHAC1 [30] 22 (-)-Epigallocatechin-3-gallate GRP78, ATF4, XBP1s, CHOP and EDEM [31] 23 Asperuloside GRP78, p-PERK, p-eIF2α, CHOP, p-IRE1, XBP1, and ATF6 [32] Tumor cell autophagy Non-small cell lung cancer 24 Ginsenoside ATF4-CHOP-AKT1-mTOR [36] 25 Guangsangon E (GSE) ROS-ERS (GRP78, IRE1α and ATF4) [37] Colorectal cancer 26 Serpentine GRP78, p -PERK, p-elF2α and CHOP [38] 27 Cryptotanshinone Cell autophagy by ERS [39] Gynecologic urogenital tumors 28 Cucurbitacin-I IRE1α-caspase 1-p-PERK-eIF2-ATF4-CHOP [40] Tumor cell invasion and metastasis…”