Mechanism of caspase-12-dependent endoplasmic reticulum stress apoptosis induced by oxymatrine in gastric cancer BGC-823 cells_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

FANG Wei , MA Shixun ,  MA Yuntao , ZHAN Weipeng , LI Yuan , LI Yiping , HU Ming

Department of General Surgery 1, Gansu Provincial Hospital, Lanzhou 730000, P. R. China;

Corresponding author：

MA Yuntao, Email: lzdxl20@sina.com

Keywords：

oxymatrine; gastric neoplasm; apoptosis; endoplasmic reticulum stress

DOI：

10.7507/1007-9424.201811043

Video：

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Objective To study effects of oxymatrine on proliferation and apoptosis of gastric cancer cell line BGC-823 and explore role of endoplasmic reticulum stress in apoptosis of gastric cancer cells induced by oxymatrine and elucidate its mechanism.Methods The gastric cancer BGC-823 cells at the logarithmic phase were divided into a control group, oxymatrine alone group (oxymatrine at 10, 30, 60 and 90 μmol/L concentrations), and combination group (oxymatrine at various concentrations combined with 2 μmol/L endoplasmic reticulum stress inhibitor salubrinal). The MTT assay was used to observe the inhibitory effect of the oxymatrine on the growth of BGC-823 cells. The flow cytometry was used to analyze the apoptosis and cell cycle. The Western blot and RT-PCR methods were used to detect the expressions of GRP78/Bip and the caspase-12 protein and gene, respectively.Results ① Compared with the control group, the oxymatrine could significantly inhibit the growth of gastric cancer BGC-823 cells in a concentration-time dependent manner (P<0.05) and its IC₅₀ (48 h) value was (59.5±0.5) μmol/L. The inhibitory effect of the combination group of 30, 60, and 90 μmol/L oxymatrine was significantly weakened as compared with the the corresponding oxymatrine alone group (P<0.05). ② The oxymatrine could significantly induce the apoptosis and arrest the G₂/M phase in the gastric cancer BGC-823 cells in a concentration-dependent manner (P<0.05). The combination group of 60 μmol/L oxymatrine could significantly decreased the apoptosis rate and the number of cells in the G₂/M phase in the gastric cancer BGC-823 cells after treating 48 h (P<0.05). ③ The protein and gene levels of GRP78/Bip and caspase-12 showed significant increases with the increase of oxymatrine concentrations in the oxymatrine alone group (except the protein and gene levels of caspase-12 at 10 μmol/L oxymatrine) as compared with the control group (P<0.05), which in the combination group of 60 μmol/L and 90 μmol/L oxymatrines were significantly decreased as compared with the corresponding oxymatrine alone group (P<0.05).Conclusion Oxymatrine can inhibit growth of human gastric cancer cell line BGC-823, which maybe related to caspase-12-dependent induction of apoptosis and up-regulation of GRP78/Bip expression, which needs further experimental verification.

Citation： FANG Wei, MA Shixun, MA Yuntao, ZHAN Weipeng, LI Yuan, LI Yiping, HU Ming. Mechanism of caspase-12-dependent endoplasmic reticulum stress apoptosis induced by oxymatrine in gastric cancer BGC-823 cells. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2019, 26(4): 399-404. doi: 10.7507/1007-9424.201811043 Copy

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3.	王建, 安华松, 宋正霞, 等. 曲妥珠单抗对SW-620人结肠癌细胞增殖凋亡的影响及其与奥沙利铂协同作用的研究. 中国普外基础与临床杂志, 2018, 25(12): 1433-1438.
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5.	Yin W, Han J, Zhang Z, et al. Aloperine protects mice against bleomycin-induced pulmonary fibrosis by attenuating fibroblast proliferation and differentiation. Sci Rep, 2018, 8(1): 6265.
6.	Yin LL, Wen XM, Lai QH, et al. Lenalidomide improvement of cisplatin antitumor efficacy on triple-negative breast cancer cells. Oncol Lett, 2018, 15(5): 6469-6474.
7.	Xue JX, Zhu ZY, Bian WH, et al. The traditional Chinese medicine Kangai injection as an adjuvant method in combination with chemotherapy for the treatment of breast cancer in Chinese patients: A meta-analysis. Evid Based Complement Alternat Med, 2018, 2018: 6305645.
8.	Xu XX, Bi JP, Ping L, et al. A network pharmacology approach to determine the synergetic mechanisms of herb couple for treating rheumatic arthritis. Drug Des Devel Ther, 2018, 12: 967-979.
9.	Meng LQ, Wang Y, Luo YH, et al. Quinalizarin induces apoptosis through reactive oxygen species (ROS)-mediated mitogen-activated protein kinase (MAPK) and Signal transducer and activator of transcription 3(STAT3) signaling pathways in colorectal cancer cells. Med Sci Monit, 2018, 24: 3710-3719.
10.	Li W, Yu X, Tan S, et al. Oxymatrine inhibits non-small cell lung cancer via suppression of EGFR signaling pathway. Cancer Med, 2018, 7(1): 208-218.
11.	Hou X, Du H, Yang R, et al. The antitumor activity screening of chemical constituents from Camellia nitidissima Chi. Int J Mol Med, 2018, 41(5): 2793-2801.
12.	Gu LL, Shen ZL, Li YL, et al. Oxymatrine causes hepatotoxicity by promoting the phosphorylation of JNK and induction of endoplasmic reticulum stress mediated by ROS in LO2 cells. Mol Cells, 2018, 41(5): 401-412.
13.	Dai JP, Wang QW, Su Y, et al. Oxymatrine inhibits influenza A virus replication and inflammation via TLR4, p38 MAPK and NF-κB pathways. Int J Mol Sci, 2018, 19(4): pii: E965.
14.	Hu Z, Qin F, Gao S, et al. Paeoniflorin exerts protective effect on radiation-induced hepatic fibrosis in rats via TGF-β1/Smads signaling pathway. Am J Transl Res, 2018, 10(3): 1012-1021.
15.	Aghvami M, Ebrahimi F, Zarei MH, et al. Matrine induction of ROS mediated apoptosis in human ALL B-lymphocytes via mitochondrial targeting. Asian Pac J Cancer Prev, 2018, 19(2): 555-560.
16.	Zhu C, Li X, Zhang B, et al. Quantitative analysis of multi-components by single marker—a rational method for the internal quality of Chinese herbal medicine. Integr Med Res, 2017, 6(1): 1-11.
17.	Zhang Y, Liang Y, He C. Anticancer activities and mechanisms of heat-clearing and detoxicating traditional Chinese herbal medicine. Chin Med, 2017, 12: 20.

1. Zhou YJ, Guo YJ, Yang XL, et al. Anti-cervical cancer role of matrine, oxymatrine and sophora flavescens alkaloid gels and its mechanism. J Cancer, 2018, 9(8): 1357-1364.
2. 朱栋良, 尹小平, 王芳元. 异鼠李素对胃癌细胞增殖及凋亡的影响. 中国普外基础与临床杂志, 2018, 25(3): 350-353.
3. 王建, 安华松, 宋正霞, 等. 曲妥珠单抗对SW-620人结肠癌细胞增殖凋亡的影响及其与奥沙利铂协同作用的研究. 中国普外基础与临床杂志, 2018, 25(12): 1433-1438.
4. Zhang B, Wang X, Li Y, et al. Matrine is identified as a novel macropinocytosis inducer by a network target approach. Front Pharmacol, 2018, 9: 10.
5. Yin W, Han J, Zhang Z, et al. Aloperine protects mice against bleomycin-induced pulmonary fibrosis by attenuating fibroblast proliferation and differentiation. Sci Rep, 2018, 8(1): 6265.
6. Yin LL, Wen XM, Lai QH, et al. Lenalidomide improvement of cisplatin antitumor efficacy on triple-negative breast cancer cells. Oncol Lett, 2018, 15(5): 6469-6474.
7. Xue JX, Zhu ZY, Bian WH, et al. The traditional Chinese medicine Kangai injection as an adjuvant method in combination with chemotherapy for the treatment of breast cancer in Chinese patients: A meta-analysis. Evid Based Complement Alternat Med, 2018, 2018: 6305645.
8. Xu XX, Bi JP, Ping L, et al. A network pharmacology approach to determine the synergetic mechanisms of herb couple for treating rheumatic arthritis. Drug Des Devel Ther, 2018, 12: 967-979.
9. Meng LQ, Wang Y, Luo YH, et al. Quinalizarin induces apoptosis through reactive oxygen species (ROS)-mediated mitogen-activated protein kinase (MAPK) and Signal transducer and activator of transcription 3(STAT3) signaling pathways in colorectal cancer cells. Med Sci Monit, 2018, 24: 3710-3719.
10. Li W, Yu X, Tan S, et al. Oxymatrine inhibits non-small cell lung cancer via suppression of EGFR signaling pathway. Cancer Med, 2018, 7(1): 208-218.
11. Hou X, Du H, Yang R, et al. The antitumor activity screening of chemical constituents from Camellia nitidissima Chi. Int J Mol Med, 2018, 41(5): 2793-2801.
12. Gu LL, Shen ZL, Li YL, et al. Oxymatrine causes hepatotoxicity by promoting the phosphorylation of JNK and induction of endoplasmic reticulum stress mediated by ROS in LO2 cells. Mol Cells, 2018, 41(5): 401-412.
13. Dai JP, Wang QW, Su Y, et al. Oxymatrine inhibits influenza A virus replication and inflammation via TLR4, p38 MAPK and NF-κB pathways. Int J Mol Sci, 2018, 19(4): pii: E965.
14. Hu Z, Qin F, Gao S, et al. Paeoniflorin exerts protective effect on radiation-induced hepatic fibrosis in rats via TGF-β1/Smads signaling pathway. Am J Transl Res, 2018, 10(3): 1012-1021.
15. Aghvami M, Ebrahimi F, Zarei MH, et al. Matrine induction of ROS mediated apoptosis in human ALL B-lymphocytes via mitochondrial targeting. Asian Pac J Cancer Prev, 2018, 19(2): 555-560.
16. Zhu C, Li X, Zhang B, et al. Quantitative analysis of multi-components by single marker—a rational method for the internal quality of Chinese herbal medicine. Integr Med Res, 2017, 6(1): 1-11.
17. Zhang Y, Liang Y, He C. Anticancer activities and mechanisms of heat-clearing and detoxicating traditional Chinese herbal medicine. Chin Med, 2017, 12: 20.

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Mechanism of caspase-12-dependent endoplasmic reticulum stress apoptosis induced by oxymatrine in gastric cancer BGC-823 cells

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