Oridonin induces ferroptosis by inhibiting gamma-glutamyl cycle in TE1 cells.
Antineoplastic Agents
/ pharmacology
Cell Line, Tumor
Cell Proliferation
/ drug effects
Chromatography, Liquid
Cysteine
Dipeptides
Diterpenes, Kaurane
/ pharmacology
Esophageal Neoplasms
Ferroptosis
Glutamate-Cysteine Ligase
Glutamates
Glutathione
/ metabolism
Humans
Iron
/ analysis
Malondialdehyde
/ analysis
Metabolome
Phospholipid Hydroperoxide Glutathione Peroxidase
Reactive Oxygen Species
/ analysis
Tandem Mass Spectrometry
gamma-Glutamyltransferase
GGT1
Oridonin
cysteine
ferroptosis
gamma-glutamyl cycle
Journal
Phytotherapy research : PTR
ISSN: 1099-1573
Titre abrégé: Phytother Res
Pays: England
ID NLM: 8904486
Informations de publication
Date de publication:
Jan 2021
Jan 2021
Historique:
received:
25
02
2020
revised:
08
07
2020
accepted:
11
07
2020
pubmed:
2
9
2020
medline:
24
2
2021
entrez:
2
9
2020
Statut:
ppublish
Résumé
Oridonin (Ori) is a natural tetracyclic diterpenoid active compound with excellent antitumor activity, but the mechanism of Ori on esophageal cancer cell, TE1, remains unclear. In this study, we examined the levels of intracellular iron, malondialdehyde, and reactive oxygen species after Ori treatment, while interfering with the effects of Ori with ferroptosis inhibitor, demonstrating that Ori's inhibition of TE1 cell proliferation is associated with ferroptosis. To understand the molecular mechanism of Ori, we performed UPLC-MS/MS metabolomics profiling on TE1 cells, which show that gamma-glutamyl amino acids (gamma-glutamylleucine, gamma-glutamylvaline), 5-oxoproline, glutamate, GSH, and GSSG are changed significantly after Ori treatment. Meanwhile, the activity of gamma-glutamyl transpeptidase 1 (GGT1) decreased. This revealed that Ori inhibited the gamma-glutamyl cycle in TE1 cells. Furthermore, we found that Ori can covalently bind to cysteine to form the conjugate oridonin-cysteine (Ori-Cys), resulting in the inhibition of glutathione synthesis, which is consistent with the decrease in the enzymatic activity of glutamate cysteine ligase catalytic subunit (GCLC). Eventually, the value of intracellular GSH/GSSG was reduced, and the enzymatic activity of the glutathione peroxidase 4 (GPX4) was significantly decreased. In conclusion, our experiments indicated that Ori can inhibit the gamma-glutamyl cycle, thereby inducing ferroptosis to exert anti-cancer activity.
Substances chimiques
Antineoplastic Agents
0
Dipeptides
0
Diterpenes, Kaurane
0
Glutamates
0
Reactive Oxygen Species
0
gamma-glutamylvaline
0
oridonin
0APJ98UCLQ
gamma-glutamyl-leucine
2566-39-4
Malondialdehyde
4Y8F71G49Q
Iron
E1UOL152H7
Phospholipid Hydroperoxide Glutathione Peroxidase
EC 1.11.1.12
gamma-Glutamyltransferase
EC 2.3.2.2
gamma-glutamyltransferase, human
EC 2.3.2.2
GCLC protein, human
EC 6.3.2.2
Glutamate-Cysteine Ligase
EC 6.3.2.2
Glutathione
GAN16C9B8O
Cysteine
K848JZ4886
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
494-503Subventions
Organisme : China Postdoctoral Science Foundation
ID : 2019M652596
Organisme : Initiation funds for postdoctoral research projects in Henan Province
ID : 1901003
Organisme : National Natural Science Foundation of China
ID : 81603114
Organisme : National Natural Science Foundation of China
ID : U1904154
Organisme : National Natural Science Foundation of China
ID : U1904163
Informations de copyright
© 2020 John Wiley & Sons Ltd.
Références
Bansal, A., Sanchez, D. J., Nimgaonkar, V., Sanchez, D., & Riscal, R. (2019). Gamma-Glutamyltransferase 1 promotes clear cell renal cell carcinoma initiation and progression. Molecular Cancer Research, 17(9), 1881-1892.
Corti, A., Franzini, M., Paolicchi, A., & Pompella, A. (2010). Gamma-glutamyltransferase of cancer cells at the crossroads of tumor progression, drug resistance and drug targeting. Anticancer Research, 30(4), 1169-1181.
Ding, Y., Ding, C., Ye, N., Liu, Z., Wold, E. A., Chen, H., … Zhou, J. (2016). Discovery and development of natural product oridonin-inspired anticancer agents. European Journal of Medicinal Chemistry, 122, 102-117.
Fan, Q. X., Wang, R., & Wang, R. L. (2007). Clinical efficacy of treatment by Rabdosia rubescens alone or in combination chemotherapy for esophageal cancer. World Chinese Journal of Digestology, 15(23), 2534-2537.
Fang, X., & Wang, H. (2019). Ferroptosis as a target for protection against cardiomyopathy. Proceedings of the National Academy of Sciences of the United States of America, 116(7), 2672-2680.
Fujii, J., Homma, T., & Kobayashi, S. (2019). Ferroptosis caused by cysteine insufficiency and oxidative insult. Free Radical Research, 1-12. https://doi.org/10.1080/10715762.2019.1666983.
Gao, F. H., Liu, F., Wei, W., Liu, L. B., Xu, M. H., Guo, Z. Y., … Wu, Y. L. (2012). Oridonin induces apoptosis and senescence by increasing hydrogen peroxide and glutathione depletion in colorectal cancer cells. International Journal of Molecular Medicine, 29(4), 649-655.
Gonzalez, E., van Liempd, S., Conde-Vancells, J., Gutierrez-de Juan, V., Perez-Cormenzana, M., Mayo, R., … Falcon-Perez, J. M. (2012). Serum UPLC-MS/MS metabolic profiling in an experimental model for acute-liver injury reveals potential biomarkers for hepatotoxicity. Metabolomics, 8(6), 997-1011.
Gu, M. M., Li, M., Gao, D., Liu, L. H., Lang, Y., Yang, S. M., … Shang, Z. F. (2018). The vanillin derivative 6-bromine-5-hydroxy-4-methoxybenzaldehyde induces aberrant mitotic progression and enhances radio-sensitivity accompanying suppression the expression of PLK1 in esophageal squamous cell carcinoma. Toxicology and Applied Pharmacology, 348, 76-84.
Guo, X., Long, P., Meng, Q., Ho, C. T., & Zhang, L. (2018). An emerging strategy for evaluating the grades of Keemun black tea by combinatory liquid chromatography-Orbitrap mass spectrometry-based untargeted metabolomics and inhibition effects on alpha-glucosidase and alpha-amylase. Food Chemistry, 246, 74-81.
Hanigan, M. H. (2014). Gamma-glutamyl transpeptidase: Redox regulation and drug resistance. Advances in Cancer Research, 122, 103-141.
He, H., Jiang, H., Chen, Y., Ye, J., Wang, A., & Wang, C. (2018). Oridonin is a covalent NLRP3 inhibitor with strong anti-inflammasome activity. Nature Communications, 9(1), 2550.
Huang, H., Wang, X. P., Li, X. H., Chen, H., Zheng, X., Lin, J. H., … Chen, P. S. (2017). Prognostic value of pretreatment serum alanine aminotransferase/aspartate aminotransferase (ALT/AST) ratio and gamma glutamyltransferase (GGT) in patients with esophageal squamous cell carcinoma. BMC Cancer, 17(1), 544.
Kang, N., Zhang, J. H., Qiu, F., Tashiro, S., Onodera, S., & Ikejima, T. (2010). Inhibition of EGFR signaling augments oridonin-induced apoptosis in human laryngeal cancer cells via enhancing oxidative stress coincident with activation of both the intrinsic and extrinsic apoptotic pathways. Cancer Letters, 294(2), 147-158.
Ku, C. M., & Lin, J. Y. (2013). Anti-inflammatory effects of 27 selected terpenoid compounds tested through modulating Th1/Th2 cytokine secretion profiles using murine primary splenocytes. Food Chemistry, 141(2), 1104-1113.
Kuo, L. M., Kuo, C. Y., Lin, C. Y., Hung, M. F., Shen, J. J., & Hwang, T. L. (2014). Intracellular glutathione depletion by oridonin leads to apoptosis in hepatic stellate cells. Molecules, 19(3), 3327-3344.
Liu, Q. Q., Chen, K., Ye, Q., Jiang, X. H., & Sun, Y. W. (2016). Oridonin inhibits pancreatic cancer cell migration and epithelial-mesenchymal transition by suppressing Wnt/beta-catenin signaling pathway. Cancer Cell International, 16, 57.
Lu, B., Chen, X. B., Ying, M. D., He, Q. J., Cao, J., & Yang, B. (2017). The role of Ferroptosis in cancer development and treatment response. Frontiers in Pharmacology, 8, 992.
Lu, S. C. (2013). Glutathione synthesis. Biochimica et Biophysica Acta, 1830(5), 3143-3153.
Mou, Y., Wang, J., Wu, J., He, D., Zhang, C., Duan, C., & Li, B. (2019). Ferroptosis, a new form of cell death: Opportunities and challenges in cancer. Journal of Hematology & Oncology, 12(1), 34.
Nordstrom, A., O'Maille, G., Qin, C., & Siuzdak, G. (2006). Nonlinear data alignment for UPLC-MS and HPLC-MS based metabolomics: Quantitative analysis of endogenous and exogenous metabolites in human serum. Analytical Chemistry, 78(10), 3289-3295.
Owona, B. A., & Schluesener, H. J. (2015). Molecular insight in the multifunctional effects of Oridonin. Drugs in R & D, 15(3), 233-244.
Peng, L., Linghu, R., & Chen, D. (2017). Inhibition of glutathione metabolism attenuates esophageal cancer progression. Experimental & Molecular Medicine, 49(4), e318.
Priolo, C., Khabibullin, D., Reznik, E., Filippakis, H., Ogorek, B., Kavanagh, T. R., … Henske, E. P. (2018). Impairment of gamma-glutamyl transferase 1 activity in the metabolic pathogenesis of chromophobe renal cell carcinoma. Proceedings of the National Academy of Sciences of the United States of America, 115(27), E6274-E6282.
Song, M., Liu, X., Liu, K., Zhao, R., Huang, H., Shi, Y., … Lee, M. H. (2018). Targeting AKT with Oridonin inhibits growth of esophageal squamous cell carcinoma in vitro and patient-derived Xenografts in vivo. Molecular Cancer Therapeutics, 17(7), 1540-1553.
Stockwell, B. R., Friedmann Angeli, J. P., Bayir, H., Bush, A. I., Conrad, M., Dixon, S. J., … Zhang, D. D. (2017). Ferroptosis: A regulated cell death nexus linking metabolism, redox biology, and disease. Cell, 171(2), 273-285.
Watanabe, M., Otake, R., Kozuki, R., Toihata, T., Takahashi, K., Okamura, A., & Imamura, Y. (2020). Recent progress in multidisciplinary treatment for patients with esophageal cancer. Surgery Today, 50(1), 12-20.
Wu, Y., Song, J., Wang, Y., Wang, X., Culmsee, C., & Zhu, C. (2019). The potential role of Ferroptosis in neonatal brain injury. Frontiers in Neuroscience, 13, 115.
Yu, Y., Fan, S. M., Song, J. K., Tashiro, S., Onodera, S., & Ikejima, T. (2012). Hydroxyl radical (.OH) played a pivotal role in oridonin-induced apoptosis and autophagy in human epidermoid carcinoma A431 cells. Biological & Pharmaceutical Bulletin, 35(12), 2148-2159.
Zhang, J., Zhou, Y., Sun, Y., Yan, H., Han, W., Wang, X., … Xu, X. (2019). Beneficial effects of Oridonin on myocardial ischemia/reperfusion injury: Insight gained by metabolomic approaches. European Journal of Pharmacology, 861, 172587.
Zhao, X., Zeng, Z., Chen, A., Lu, X., Zhao, C., Hu, C., … Xu, G. (2018). Comprehensive strategy to construct in-house database for accurate and batch identification of small molecular metabolites. Analytical Chemistry, 90(12), 7635-7643.