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Walsuronoid B induces mitochondrial and lysosomal dysfunction leading to apoptotic rather than autophagic cell death via ROS/p53 signaling pathways in liver cancer.
Biochem Pharmacol. 2017 10 15; 142:71-86.BP

Abstract

Walsuronoid B is a limonoid compound extracted from Walsura robusta. Previous studies have shown that limonoid compounds possess anti-cancer potential, although the molecular mechanism of this activity remains elusive. In this study, we demonstrated for the first time that walsuronoid B inhibited cell proliferation in several human cancer lines. Liver cancer cells (HepG2 and Bel-7402) were chosen for their high sensitivity to walsuronoid B. Walsuronoid B induced cell death through G2/M phase arrest and apoptosis and induced the accumulation of autophagosomes through the suppression of mTOR signaling, which serves as a cell survival mechanism and prevents cell death. We further examined the molecular mechanisms and found that walsuronoid B-induced dysfunction of the mitochondria and lysosomes rather than the endoplasmic reticulum contributed to its cell death effect. Walsuronoid B enhanced the generation of hydrogen peroxide, nitric oxide and superoxide anion radical, resulting in elevated levels of reactive oxygen species (ROS). In addition, ROS induced by walsuronoid B upregulated p53 levels; conversely, p53 stimulated ROS. These results suggested that ROS and p53 reciprocally promoted each other's production and cooperated to induce liver cancer cell death. We found that the induction of ROS and p53 significantly triggered G2/M phase arrest and mitochondrial and lysosomal apoptosis. Finally, walsuronoid B suppressed tumor growth in vivo with few side effects. In summary, our findings demonstrated that walsuronoid B caused G2/M phase arrest and induced mitochondrial and lysosomal apoptosis through the ROS/p53 signaling pathway in human liver cancer cells in vitro and in vivo.

Authors+Show Affiliations

Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China. Electronic address: lykong@cpu.edu.cn.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

28673807

Citation

Geng, Ya-di, et al. "Walsuronoid B Induces Mitochondrial and Lysosomal Dysfunction Leading to Apoptotic Rather Than Autophagic Cell Death Via ROS/p53 Signaling Pathways in Liver Cancer." Biochemical Pharmacology, vol. 142, 2017, pp. 71-86.
Geng YD, Zhang C, Lei JL, et al. Walsuronoid B induces mitochondrial and lysosomal dysfunction leading to apoptotic rather than autophagic cell death via ROS/p53 signaling pathways in liver cancer. Biochem Pharmacol. 2017;142:71-86.
Geng, Y. D., Zhang, C., Lei, J. L., Yu, P., Xia, Y. Z., Zhang, H., Yang, L., & Kong, L. Y. (2017). Walsuronoid B induces mitochondrial and lysosomal dysfunction leading to apoptotic rather than autophagic cell death via ROS/p53 signaling pathways in liver cancer. Biochemical Pharmacology, 142, 71-86. https://doi.org/10.1016/j.bcp.2017.06.134
Geng YD, et al. Walsuronoid B Induces Mitochondrial and Lysosomal Dysfunction Leading to Apoptotic Rather Than Autophagic Cell Death Via ROS/p53 Signaling Pathways in Liver Cancer. Biochem Pharmacol. 2017 10 15;142:71-86. PubMed PMID: 28673807.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Walsuronoid B induces mitochondrial and lysosomal dysfunction leading to apoptotic rather than autophagic cell death via ROS/p53 signaling pathways in liver cancer. AU - Geng,Ya-di, AU - Zhang,Chao, AU - Lei,Jian-Li, AU - Yu,Pei, AU - Xia,Yuan-Zheng, AU - Zhang,Hao, AU - Yang,Lei, AU - Kong,Ling-Yi, Y1 - 2017/07/01/ PY - 2017/04/21/received PY - 2017/06/29/accepted PY - 2017/7/5/pubmed PY - 2017/10/19/medline PY - 2017/7/5/entrez KW - Apoptosis KW - Bafilomycin A1 (PubChem CID: 6436223) KW - Cell cycle arrest KW - Cisplatin (PubChem CID: 2767) KW - Cyclosporin A (PubChem CID: 5284373) KW - Liver cancer cell KW - ROS KW - Sodium phenylbutyrate (PubChem CID: 5258) KW - Walsuronoid B KW - Walsuronoid B (PubChem CID: 16724460) KW - p53 SP - 71 EP - 86 JF - Biochemical pharmacology JO - Biochem. Pharmacol. VL - 142 N2 - Walsuronoid B is a limonoid compound extracted from Walsura robusta. Previous studies have shown that limonoid compounds possess anti-cancer potential, although the molecular mechanism of this activity remains elusive. In this study, we demonstrated for the first time that walsuronoid B inhibited cell proliferation in several human cancer lines. Liver cancer cells (HepG2 and Bel-7402) were chosen for their high sensitivity to walsuronoid B. Walsuronoid B induced cell death through G2/M phase arrest and apoptosis and induced the accumulation of autophagosomes through the suppression of mTOR signaling, which serves as a cell survival mechanism and prevents cell death. We further examined the molecular mechanisms and found that walsuronoid B-induced dysfunction of the mitochondria and lysosomes rather than the endoplasmic reticulum contributed to its cell death effect. Walsuronoid B enhanced the generation of hydrogen peroxide, nitric oxide and superoxide anion radical, resulting in elevated levels of reactive oxygen species (ROS). In addition, ROS induced by walsuronoid B upregulated p53 levels; conversely, p53 stimulated ROS. These results suggested that ROS and p53 reciprocally promoted each other's production and cooperated to induce liver cancer cell death. We found that the induction of ROS and p53 significantly triggered G2/M phase arrest and mitochondrial and lysosomal apoptosis. Finally, walsuronoid B suppressed tumor growth in vivo with few side effects. In summary, our findings demonstrated that walsuronoid B caused G2/M phase arrest and induced mitochondrial and lysosomal apoptosis through the ROS/p53 signaling pathway in human liver cancer cells in vitro and in vivo. SN - 1873-2968 UR - https://www.unboundmedicine.com/medline/citation/28673807/Walsuronoid_B_induces_mitochondrial_and_lysosomal_dysfunction_leading_to_apoptotic_rather_than_autophagic_cell_death_via_ROS/p53_signaling_pathways_in_liver_cancer_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0006-2952(17)30474-4 DB - PRIME DP - Unbound Medicine ER -