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Brazilin induces FOXO3A-dependent autophagic cell death by disturbing calcium homeostasis in osteosarcoma cells.
Cancer Chemother Pharmacol. 2018 09; 82(3):479-491.CC

Abstract

PURPOSE

Osteosarcoma is a common primary malignant bone tumour, and its cure rate has stagnated over the past 25-30 years. Brazilin, a purified natural product from sappan wood (Caesalpinia sappan L.), has been proved to possess potent anti-cancer effects. In this study, we investigated the anti-cancer effect of brazilin on human osteosarcoma and elucidated the underlying mechanisms.

METHODS

We exposed MG-63 cells to different concentrations of brazilin (5, 10 and 20 µM) for 24 h. Western blotting, immunocytofluorescence, luciferase reporter assays, and RT-PCR were used to evaluate whether brazilin activates FOXO family-dependent autophagy.

RESULTS

Brazilin increased autophagic flux in the human osteosarcoma cell line MG-63, as evidenced by the upregulation of LC3-II and the downregulation of P62/SQSTM1. Moreover, the pharmacological or genetic blockade of autophagy decreased brazilin-induced cell death, indicating that brazilin triggered autophagic cell death in MG-63 cells. Specifically, brazilin induced FOXO3A(Ser7) phosphorylation, activated FOXO3A nuclear translocation and increased FOXO3A reporter activity, which contributed to the expression of autophagy-related genes and subsequently initiated autophagic cell death in MG-63 cells. Importantly, the increased expression and nuclear translocation of FOXO3A were tightly related to the disturbance of calcium homeostasis, which could be prevented by chelating intracellular calcium.

CONCLUSIONS

Taken together, these data demonstrate that brazilin induces osteosarcoma cell death by inducing excessive autophagy, which is mediated through the Ca2+-FOXO3A pathway. Our study provides a new anti-tumour mechanism for brazilin treatment in osteosarcoma patients.

Authors+Show Affiliations

Department of Orthopaedic Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510080, Guangdong, China.Department of Orthopaedic Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510080, Guangdong, China.Department of Orthopaedic Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510080, Guangdong, China.Department of Hepato-Biliary Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, Guangdong, China.Department of Orthopaedic Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510080, Guangdong, China.Department of Spine Surgery, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510000, Guangdong, China. xiepeigen120@163.com.Department of Orthopaedics, The Affiliated Zhuzhou Hospital Xiangya Medical College of Central South University, Zhuzhou, 412007, Hunan, China. bowenwusci2018@sina.com.

Pub Type(s)

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

Language

eng

PubMed ID

29987368

Citation

Kang, Yan, et al. "Brazilin Induces FOXO3A-dependent Autophagic Cell Death By Disturbing Calcium Homeostasis in Osteosarcoma Cells." Cancer Chemotherapy and Pharmacology, vol. 82, no. 3, 2018, pp. 479-491.
Kang Y, He P, Wang H, et al. Brazilin induces FOXO3A-dependent autophagic cell death by disturbing calcium homeostasis in osteosarcoma cells. Cancer Chemother Pharmacol. 2018;82(3):479-491.
Kang, Y., He, P., Wang, H., Ye, Y., Li, X., Xie, P., & Wu, B. (2018). Brazilin induces FOXO3A-dependent autophagic cell death by disturbing calcium homeostasis in osteosarcoma cells. Cancer Chemotherapy and Pharmacology, 82(3), 479-491. https://doi.org/10.1007/s00280-018-3633-5
Kang Y, et al. Brazilin Induces FOXO3A-dependent Autophagic Cell Death By Disturbing Calcium Homeostasis in Osteosarcoma Cells. Cancer Chemother Pharmacol. 2018;82(3):479-491. PubMed PMID: 29987368.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Brazilin induces FOXO3A-dependent autophagic cell death by disturbing calcium homeostasis in osteosarcoma cells. AU - Kang,Yan, AU - He,Peiheng, AU - Wang,Hua, AU - Ye,Yibiao, AU - Li,Xing, AU - Xie,Peigen, AU - Wu,Bowen, Y1 - 2018/07/09/ PY - 2018/03/26/received PY - 2018/06/26/accepted PY - 2018/7/11/pubmed PY - 2019/8/10/medline PY - 2018/7/11/entrez KW - Autophagy KW - Brazilin KW - Calcium KW - FOXO KW - Osteosarcoma SP - 479 EP - 491 JF - Cancer chemotherapy and pharmacology JO - Cancer Chemother. Pharmacol. VL - 82 IS - 3 N2 - PURPOSE: Osteosarcoma is a common primary malignant bone tumour, and its cure rate has stagnated over the past 25-30 years. Brazilin, a purified natural product from sappan wood (Caesalpinia sappan L.), has been proved to possess potent anti-cancer effects. In this study, we investigated the anti-cancer effect of brazilin on human osteosarcoma and elucidated the underlying mechanisms. METHODS: We exposed MG-63 cells to different concentrations of brazilin (5, 10 and 20 µM) for 24 h. Western blotting, immunocytofluorescence, luciferase reporter assays, and RT-PCR were used to evaluate whether brazilin activates FOXO family-dependent autophagy. RESULTS: Brazilin increased autophagic flux in the human osteosarcoma cell line MG-63, as evidenced by the upregulation of LC3-II and the downregulation of P62/SQSTM1. Moreover, the pharmacological or genetic blockade of autophagy decreased brazilin-induced cell death, indicating that brazilin triggered autophagic cell death in MG-63 cells. Specifically, brazilin induced FOXO3A(Ser7) phosphorylation, activated FOXO3A nuclear translocation and increased FOXO3A reporter activity, which contributed to the expression of autophagy-related genes and subsequently initiated autophagic cell death in MG-63 cells. Importantly, the increased expression and nuclear translocation of FOXO3A were tightly related to the disturbance of calcium homeostasis, which could be prevented by chelating intracellular calcium. CONCLUSIONS: Taken together, these data demonstrate that brazilin induces osteosarcoma cell death by inducing excessive autophagy, which is mediated through the Ca2+-FOXO3A pathway. Our study provides a new anti-tumour mechanism for brazilin treatment in osteosarcoma patients. SN - 1432-0843 UR - https://www.unboundmedicine.com/medline/citation/29987368/Brazilin_induces_FOXO3A_dependent_autophagic_cell_death_by_disturbing_calcium_homeostasis_in_osteosarcoma_cells_ L2 - https://dx.doi.org/10.1007/s00280-018-3633-5 DB - PRIME DP - Unbound Medicine ER -