Celastrus Orbiculatus Extracts Inhibit the Metastasis through Attenuating PI3K/Akt/mTOR Signaling Pathway in Human Gastric Cancer

Author(s): Yayun Qian*, Yan Yan, Hongmei Lu, Tingting Zhou, Mengying Lv, Chuanci Fang, Jingjing Hou, Wenyuan Li, Xiwen Chen, Hui Sun, Yajuan Li, Zheng Wang, Nan Zhao, Yajuan Gu, Yongling Ding*, Yanqing Liu*.

Journal Name: Anti-Cancer Agents in Medicinal Chemistry
(Formerly Current Medicinal Chemistry - Anti-Cancer Agents)

Volume 19 , Issue 14 , 2019

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Graphical Abstract:


Abstract:

Background: Rapamycin receptor inhibitors have been applied in the clinic and achieved satisfactory therapeutic effect recently. The mechanisms did not clearly show how the Celastrus orbiculatus Extracts (COE) inhibited the expression of the mammalian Target of Rapamycin (mTOR) in human gastric cancer cells. The aim of this study was to investigate whether the COE inhibited the metastasis through the mTOR signaling pathway in human gastric cancer MGC-803 cells.

Methods: The abnormal expression level of mTOR protein was detected by immunohistochemistry in human gastric cancer tissue. The MGC-803/mTOR- cells were constructed by knockdown of mTOR using lentivirus infection technique. The human gastric cancer MGC-803/mTOR- cells were treated with different concentrations (20, 40, 80 μg/ml) of COE for 24 hours. The ability of cell metastasis was analyzed by the cell invasion and migration assay. The expression levels of PI3K/Akt/mTOR signaling pathway were detected by Western Blotting.

Results: COE inhibited the proliferation, invasion and migration of MGC-803/mTOR- cells in a concentrationdependent manner. The expression of E-cadherin protein increased, and the expression of N-cadherin and Vimentin decreased simultaneously in the MGC-803/mTOR- cells. 4EBP1, p-4EBP1, P70S6k, p-P70S6k, mTOR, p-mTOR, PI3K and Akt proteins in MGC-803/mTOR- cells were reduced in a dose-dependent manner.

Conclusion: COE could not only inhibit cell growth, invasion and migration, but also inhibit the epithelialmesenchymal transition of gastric cancer cells. The molecular mechanism of COE inhibited the metastasis which may be related to the PI3K/Akt/mTOR signal pathway. This study provides ideas for the development of new anti-gastric cancer drugs.

Keywords: Celastrus orbiculatus, human gastric cancer, metastasis, mTOR, epithelial-mesenchymal transition, PI3K.

[1]
Ferlay, J.; Soerjomataram, I.; Dikshit, R.; Eser, S.; Mathers, C.; Rebelo, M.; Parkin, D.M.; Forman, D.; Bray, F. Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012. Int. J. Cancer, 2015, 136(5), E359-E386.
[2]
Coburn, N.; Cosby, R.; Klein, L.; Knight, G.; Malthaner, R.; Mamazza, J.; Mercer, C.D.; Ringash, J. Staging and surgical approaches in gastric cancer: A systematic review. Cancer Treat. Rev., 2018, 63, 104-115.
[3]
Schwarz, R.E. Clinical trends and effects on quality metrics for surgical gastroesophageal cancer care. Transl. Gastroenterol. Hepatol., 2018, 3, 43.
[4]
Duong, T.T.; Vo, D.T.; Nakayama, T.; Mukaisho, K.I.; Bamba, M.; Nguyen, T.S.; Sugihara, H. Rapidly and slowly growing lineages in chromosomal instability-type gland-forming gastric carcinomas as revealed by multisampling analysis of DNA copy-number profile. Pathobiology, 2019, 86(2-3), 118-127.
[5]
Nishibeppu, K.; Komatsu, S.; Ichikawa, D.; Imamura, T.; Kosuga, T.; Okamoto, K.; Konishi, H.; Shiozaki, A.; Fujiwara, H.; Otsuji, E. Venous invasion as a risk factor for recurrence after gastrectomy followed by chemotherapy for stage III gastric cancer. BMC Cancer, 2018, 18(1), 108.
[6]
Gockel, I.; Jansen-Winkeln, B.; Haase, L.; Rhode, P.; Mehdorn, M.; Niebisch, S.; Moulla, Y.; Lyros, O.; Lordick, F.; Schierle, K.; Wittekind, C.; Thieme, R. Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC) in gastric cancer patients with Peritoneal Metastasis (PM): Results of a single-center experience and register study. J. Gastric Cancer, 2018, 18(4), 379-391.
[7]
Huang, Y.K.; Kang, W.M.; Ma, Z.Q.; Liu, Y.Q.; Zhou, L.; Yu, J.C. NUCKS1 promotes gastric cancer cell aggressiveness by upregulating IGF-1R and subsequently activating the PI3K/Akt/mTOR signaling pathway. Carcinogenesis, 2019, 40(2), 370-379.
[8]
Huang, T.; Liu, D.; Wang, Y.; Li, P.; Sun, L.; Xiong, H.; Dai, Y.; Zou, M.; Yuan, X.; Qiu, H. FGFR2 promotes gastric cancer progression by inhibiting the expression of thrombospondin4 via PI3K-Akt-Mtor pathway. Cell. Physiol. Biochem., 2018, 50(4), 1332-1345.
[9]
Wang, X.; Jiao, X.; Meng, Y.; Chen, H.; Griffin, N.; Gao, X.; Shan, F. Methionine enkephalin (MENK) inhibits human gastric cancer through regulating tumor associated macrophages (TAMs) and PI3K/AKT/mTOR signaling pathway inside cancer cells. Int. Immunopharmacol., 2018, 65, 312-322.
[10]
Chen, S.; Wu, J.; Jiao, K.; Wu, Q.; Ma, J.; Chen, D.; Kang, J.; Zhao, G.; Shi, Y.; Fan, D.; Zhao, G. MicroRNA-495-3p inhibits multidrug resistance by modulating autophagy through GRP78/ mTOR axis in gastric cancer. Cell Death Dis., 2018, 9(11), 1070.
[11]
Qian, Y.; Yang, T.; Zhao, X.; Yan, Y.; Li, W.; Fang, C.; Hou, J.; Tao, L.; Liu, Y. Celastrus orbiculatus extracts induce apoptosis in mTOR-overexpressed human hepatocellular carcinoma HepG2 cells. BMC Complement. Altern. Med., 2018, 18(1), 328.
[12]
Wang, W.; Zhou, Y.; Yao, Q.; Liu, W.; Xiang, L.; Ni, T.; Dai, X.; Liu, Y. Celastrus orbiculatus extract potentiates the sensitivity of cisplatin via caspase-depenent apoptosis in gastric cancer. Anticancer. Agents Med. Chem., 2018, 18(15), 2206-2211.
[13]
Qian, Y.Y.; Shi, Y.Y.; Lu, S.H.; Yang, T.; Zhao, X.Y.; Yan, Y.; Li, W.Y.; Liu, Y.Q. Extracts of Celastrus orbiculatus inhibit cancer metastasis by down-regulating epithelial-mesenchymal transition in hypoxia-induced human hepatocellular carcinoma cells. Chin. J. Integr. Med., 2019, 25(5), 334-341.
[14]
Zhu, Y.D.; Hu, L.; Li, P.; Zhang, M.; Liu, Y.Q. Effects of Celastrus orbiculatus on epithelial mesenchymal transition in gastric mucosal epithelial cells by inhibiting Lgr5 expression from rats with gastric precancerous lesions. Am. J. Chin. Med., 2018, 46(5), 1129-1143.
[15]
Wang, X.; Huang, Y.; Chen, Y.; Ma, Y.; Yang, F.; Qian, Y.; Dai, X.; Tao, L.; Wang, H.; Guo, R.; Liu, Y. Efficacy of extracts of Celastrus orbiculatus in suppressing migration and invasion by inhibiting the EZH2/ROCK1 signaling pathway in human nasopharyngeal carcinoma. Oncol. Lett., 2018, 15(5), 6695-6700.
[16]
Jin, F.; Zhu, G.; Li, D.; Ni, T.; Dai, X.; Wang, H.; Feng, J.; Qian, Y.; Yang, L.; Guo, S.; Hisamitsu, T.; Liu, Y. Celastrus orbiculatus extracts induce cell cycle arrest and apoptosis in human esophageal squamous carcinoma ECA-109 cells in vitro via the PI3K/AKT/ mTOR signaling pathway. Oncol. Lett., 2018, 15(2), 1591-1599.
[17]
Qian, Y.; Lu, S.; Shi, Y.; Zhao, X.; Yang, T.; Jin, F.; Liu, Y. Celastrus orbiculatus extracts induce apoptosis and inhibit invasion by targeting the maspin gene in human gastric adenocarcinoma cells. Oncol. Lett., 2018, 15(1), 243-249.
[18]
Wang, H.; Gu, H.; Feng, J.; Qian, Y.; Yang, L.; Jin, F.; Wang, X.; Chen, J.; Shi, Y.; Lu, S.; Zhao, M.; Liu, Y. Celastrus orbiculatus extract suppresses the epithelial-mesenchymal transition by mediating cytoskeleton rearrangement via inhibition of the Cofilin 1 signaling pathway in human gastric cancer. Oncol. Lett., 2017, 14(3), 2926-2932.
[19]
Li, J.; Yang, J.; Lu, F.; Qi, Y.; Liu, Y.; Sun, Y.; Wang, Q. Chemical constituents from the stems of Celastrus orbiculatus. Chin. J. Nat. Med., 2012, 10(4), 279-283.
[20]
Ma, H.Y.; Liu, X.Z.; Liang, C.M. Inflammatory microenvironment contributes to epithelial-mesenchymal transition in gastric cancer. World J. Gastroenterol., 2016, 22(29), 6619-6628.
[21]
Sun, J.; Xu, Z.; Lv, H.; Wang, Y.; Wang, L.; Ni, Y.; Wang, X.; Hu, C.; Chen, S.; Teng, F.; Chen, W.; Cheng, X. eIF5A2 regulates the resistance of gastric cancer cells to cisplatin via induction of EMT. Am. J. Transl. Res., 2018, 10(12), 4269-4279.
[22]
Huang, L.; Wu, R.L.; Xu, A.M. Epithelial-mesenchymal transition in gastric cancer. Am. J. Transl. Res., 2015, 7(11), 2141-2158.
[23]
Yu, Y.; Hou, L.; Song, H.; Xu, P.; Sun, Y.; Wu, K. Akt/AMPK/mTOR pathway was involved in the autophagy induced by vitamin E succinate in human gastric cancer SGC-7901 cells. Mol. Cell. Biochem., 2017, 424(1-2), 173-183.
[24]
Qi, H.Y.; Qu, X.J.; Liu, J.; Hou, K.Z.; Fan, Y.B.; Che, X.F.; Liu, Y.P. Bufalin induces protective autophagy by Cbl-b regulating mTOR and ERK signaling pathways in gastric cancer cells. Cell Biol. Int., 2019, 43(1), 33-43.
[25]
Zhang, Z.; Miao, L.; Wu, X.; Liu, G.; Peng, Y.; Xin, X.; Jiao, B.; Kong, X. Carnosine inhibits the proliferation of human gastric carcinoma cells by retarding Akt/mTOR/p70S6K signaling. J. Cancer, 2014, 5(5), 382-389.
[26]
Chen, D.; Liu, G.; Xu, N.; You, X.; Zhou, H.; Zhao, X.; Liu, Q. Knockdown of ARK5 expression suppresses invasion and metastasis of gastric cancer. Cell. Physiol. Biochem., 2017, 42(3), 1025-1036.
[27]
Sobhani, N.; Generali, D.; Zanconati, F.; Bortul, M.; Scaggiante, B. Current status of PI3K-mTOR inhibition in hormone-receptor positive, HER2-negative breast cancer. World J. Clin. Oncol., 2018, 9(8), 172-179.
[28]
Xu, X.; Jiang, J.; Yao, L.; Ji, B. Silencing the FOLR2 gene inhibits cell proliferation and increases apoptosis in the NCI-H1650 non-small cell lung cancer cell line via inhibition of AKT/mammalian Target of Rapamycin (mTOR)/Ribosomal Protein S6 Kinase 1 (S6K1) signaling. Med. Sci. Monit., 2018, 24, 8064-8073.


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Article Details

VOLUME: 19
ISSUE: 14
Year: 2019
Page: [1754 - 1761]
Pages: 8
DOI: 10.2174/1871520619666190731162722
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