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Matrine inhibits the growth and induces apoptosis of osteosarcoma cells in vitro by inactivating the Akt pathway

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Tumor Biology

Abstract

Matrine, a natural product, has been demonstrated to be a promising chemotherapeutic drug for some cancers. Using flow cytometric analysis of the cell cycle and apoptosis, we found that matrine inhibited the proliferation and induced apoptosis in the human osteosarcoma (OS) cell lines MG63, HOS, U2OS, and SAOS2 in vitro in a dose-dependent manner. We therefore assessed the role of the serine/threonine kinase Akt in the regulation of matrine-mediated cell growth inhibition and apoptosis induction in human OS cell lines. After treatment for 48 h, matrine induced G0/G1-stage cell cycle arrest in MG63, U2OS, and SAOS2 cells associated with an increase in the expression of p27Kip1 and a decrease in the expression of Akt, glycogen synthase kinase 3 (GSK3)-β (Ser9), and cyclin D1. Furthermore, the pro-apoptotic factor Bax was upregulated. Overall, our findings suggest that matrine may be an effective anti-osteosarcoma drug due to its ability to inhibit proliferation and induce apoptosis in OS cells, possibly through the involvement of Akt signaling.

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References

  1. Li Y, Wang B, Zhou C, Bi Y. Matrine induces apoptosis in angiotensin II-stimulated hyperplasia of cardiac fibroblasts: effects on Bcl-2/Bax expression and caspase-3 activation. Basic Clin Pharmacol Toxicol. 2007;101:1–8.

    Article  CAS  PubMed  Google Scholar 

  2. Sun YN, Xu B, Huang ZQ, Huang CX. Effect of matrine on levels of TGF-β1, TNF-α, HA and PcIII in sera of chronic hepatitis B patients. Chin J Mod Med. 2004;14:41–5.

    CAS  Google Scholar 

  3. Li X, Zhou R, Zheng P, Yan L, Wu Y, Xiao X, et al. Cardioprotective effect of matrine on isoproterenol-induced cardiotoxicity in rats. J Pharm Pharmacol. 2010;62:514–20.

    Article  CAS  PubMed  Google Scholar 

  4. Liang CZ, Zhang JK, Shi Z, Liu B, Shen CQ, Tao HM. Matrine induces caspase-dependent apoptosis in human osteosarcoma cells in vitro and in vivo through the upregulation of Bax and Fas/FasL and downregulation of Bcl-2. Cancer Chemother Pharmacol. 2012;69:317–31.

    Article  CAS  PubMed  Google Scholar 

  5. Luo C, Zhu Y, Jiang T, Lu X, Zhang W, Jing Q, et al. Matrine induced gastric cancer MKN45 cells apoptosis via increasing pro-apoptotic molecules of Bcl-2 family. Toxicology. 2007;229:245–52.

    Article  CAS  PubMed  Google Scholar 

  6. Zhang L, Wang T, Wen X, Wei Y, Peng X, Li H, et al. Effect of matrine on HeLa cell adhesion and migration. Eur J Pharmacol. 2007;563:69–76.

    Article  CAS  PubMed  Google Scholar 

  7. Yu P, Liu Q, Liu K, Yagasaki K, Wu E, Zhang G. Matrine suppresses breast cancer cell proliferation and invasion via VEGF-Akt-NF-kappaB signaling. Cytotechnology. 2009;59:219–29.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Han Y, Zhang S, Wu J, Yu K, Zhang Y, Yin L, et al. Matrine induces apoptosis of human multiple myeloma cells via activation of the mitochondrial pathway. Leuk Lymphoma. 2010;51:1337–46.

    Article  CAS  PubMed  Google Scholar 

  9. Liu T, Song Y, Chen H, Pan S, Sun X. Matrine inhibits proliferation and induces apoptosis of pancreatic cancer cells in vitro and in vivo. Biol Pharm Bull. 2010;33:1740–5.

    Article  CAS  PubMed  Google Scholar 

  10. Kandel ES, Hay N. The regulation and activities of the multifunctional serine/threonine kinase Akt/PKB. Exp Cell Res. 1999;253:210–29.

    Article  CAS  PubMed  Google Scholar 

  11. Al-Shami A, Naccache PH. Granulocyte-macrophage colony-stimulating factor-activated signaling pathways in human neutrophils. Involvement of Jak2 in the stimulation of phosphatidylinositol 3-kinase. J Biol Chem. 1999;274:5333–8.

    Article  CAS  PubMed  Google Scholar 

  12. Gardai S, Whitlock BB, Helgason C, Ambruso D, Fadok V, Bratton D, et al. Activation of SHIP by NADPH oxidase-stimulated Lyn leads to enhanced apoptosis in neutrophils. J Biol Chem. 2002;277:5236–46.

    Article  CAS  PubMed  Google Scholar 

  13. Hideshima T, Nakamura N, Chauhan D, Anderson KC. Biologic sequelae of interleukin-6 induced PI3-K/Akt signaling in multiple myeloma. Oncogene. 2001;20:5991–6000.

    Article  CAS  PubMed  Google Scholar 

  14. Ye X, Guo Y, Zhang Q, Chen W, Hua X, Liu W, et al. βKlotho suppresses tumor growth in hepatocellular carcinoma by regulating Akt/GSK-3β/cyclin D1 signaling pathway. PLoS One. 2013;8:e55615.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Lu M, Gong X, Lu Y, Guo J, Wang C, Pan Y. Molecular cloning and functional characterization of a cell-permeable superoxide dismutase targeted to lung adenocarcinoma cells. Inhibition cell proliferation through the Akt/p27kip1 pathway. J Biol Chem. 2006;281:13620–7.

    Article  CAS  PubMed  Google Scholar 

  16. Gibson S, Tu S, Oyer R, Anderson SM, Johnson GL. Epidermal growth factor protects epithelial cells against Fas-induced apoptosis. Requirement for Akt activation. J Biol Chem. 1999;274:17612–8.

    Article  CAS  PubMed  Google Scholar 

  17. Datta SR, Brunet A, Greenberg ME. Cellular survival: a play in three Akts. Genes Dev. 1999;13:2905–27.

    Article  CAS  PubMed  Google Scholar 

  18. Aikin R, Rosenberg L, Maysinger D. Phosphatidylinositol 3-kinase signaling to Akt mediates survival in isolated canine islets of Langerhans. Biochem Biophys Res Commun. 2000;277:455–61.

    Article  CAS  PubMed  Google Scholar 

  19. Yamaguchi H, Wang HG. The protein kinase PKB/Akt regulates cell survival and apoptosis by inhibiting Bax conformational change. Oncogene. 2001;20:7779–86.

    Article  CAS  PubMed  Google Scholar 

  20. Tsuruta F, Masuyama N, Gotoh Y. The phosphatidylinositol 3-kinase-Akt pathway, PI3K suppresses Bax translocation to mitochondria. J Biol Chem. 2002;277:14040–7.

    Article  CAS  PubMed  Google Scholar 

  21. Zhao W, Zhou SF, Zhang ZPXGP, Li XB, Yan JL. Gambogic acid inhibits the growth of osteosarcoma cells in vitro by inducing apoptosis and cell cycle arrest. Oncol Rep. 2011;25:1289–95.

    CAS  PubMed  Google Scholar 

  22. Wang JS, Ji AF, Wan HJ, Lu YL, Yang JZ, Ma LL, et al. Gene silencing of beta-catenin by RNAi inhibits proliferation of human esophageal cancer cells by inducing G0/G1 cell cycle arrest. Asian Pac J Cancer Prev. 2012;13:2527–32.

    Article  PubMed  Google Scholar 

  23. Hernandez-Hernandez OT, Camacho-Arroyo I. Regulation of gene expression by progesterone in cancer cells: effects on cyclin D1, EGFR and VEGF. Mini-Rev Med Chem. 2013;13:635–42.

    Article  CAS  PubMed  Google Scholar 

  24. Jiang QQ, Liu B, Yuan T. MicroRNA-16 inhibits bladder cancer proliferation by targeting cyclin D1. Asian Pac J Cancer Prev. 2013;14:4127–30.

    Article  PubMed  Google Scholar 

  25. Zhu P, Chen JM, Chen SZ, Zhang C, Zheng SY, Long G, et al. Matrine inhibits vascular smooth muscle cell proliferation by modulating the expression of cell cycle regulatory genes. Acta Pharmacol Sin. 2010;31:1329–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Zhang JQ, Li YM, Liu T, He WT, Chen YT, Chen XH, et al. Antitumor effect of matrine in human hepatoma G2 cells by inducing apoptosis and autophagy. World J Gastroenterol. 2010;16:4281–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Lindsten T, Ross AJ, King A, Zong WX, Rathmell JC, Shiels HA, et al. The combined functions of proapoptotic Bcl-2 family members Bak and Bax are essential for normal development of multiple tissues. Mol Cell. 2000;6:1389–99.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Kennedy SG, Kandel ES, Cross TK, Hay N. Akt/Protein kinase B inhibits cell death by preventing the release of cytochrome c from mitochondria. Mol Cell Biol. 1999;19:5800–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Gardai SJ, Hildeman DA, Frankel SK, Whitlock BB, Frasch SC, Borregaard N, et al. Phosphorylation of Bax Ser184 by Akt regulates its activity and apoptosis in neutrophils. J Biol Chem. 2004;279:21085–95.

    Article  CAS  PubMed  Google Scholar 

  30. Merhi F, Tang R, Piedfer M, Mathieu J, Bombarda I, Zaher M, et al. Hyperforin inhibits Akt1 kinase activity and promotes caspase-mediated apoptosis involving Bad and Noxa activation in human myeloid tumor cells. PLoS One. 2011;6:e25963.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Segerstrom L, Baryawno N, Sveinbjörnsson B, Wickström M, Elfman L, Kogner P, et al. Effects of small molecule inhibitors of PI3K/Akt/mTOR signaling on neuroblastoma growth in vitro and in vivo. Int J Cancer. 2011;129:2958–65.

    Article  PubMed  Google Scholar 

  32. Yeramian A, Sorolla A, Velasco A, Santacana M, Dolcet X, Valls J, et al. Inhibition of activated receptor tyrosine kinases by Sunitinib induces growth arrest and sensitizes melanoma cells to Bortezomib by blocking Akt pathway. Int J Cancer. 2012;130:967–78.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

We thank Dr. Hua Chen and Prof. Shang-Ha Pan (The First Affiliated Hospital of Harbin Medical University) for support with experiments. This study was supported by the National Natural Scinece Foundation of China (Grant No.81441081) and the Science and Technology Research Foundation of Heilongjiang Provincial Education Department (Grant No. 12521256).

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Authors and Affiliations

  1. Department of Orthopedics, The Second Affiliated Hospital of Harbin Medical University, 148 Baojian Road, Harbin, 150081, China

    Gong-Ping Xu, Wei Zhao, Jin-Peng Zhuang, Jia-Ning Zu, Duan-Yang Wang, Fei Han, Zhi-Peng Zhang & Jing-Long Yan

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  1. Gong-Ping Xu
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  2. Wei Zhao
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Corresponding authors

Correspondence to Zhi-Peng Zhang or Jing-Long Yan.

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Gong-Ping Xu and Wei Zhao contributed equally to this work.

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Xu, GP., Zhao, W., Zhuang, JP. et al. Matrine inhibits the growth and induces apoptosis of osteosarcoma cells in vitro by inactivating the Akt pathway. Tumor Biol. 36, 1653–1659 (2015). https://doi.org/10.1007/s13277-014-2764-5

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  • DOI: https://doi.org/10.1007/s13277-014-2764-5

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