Diosgenin Glucoside Inhibits the Progression of Osteosarcoma MG-63 by Regulating the PI3K/AKT/mTOR Pathway


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Background: Trillium tschonoskii Maxim (TTM) exerts antitumor effects on a variety of tumour cells. However, the antitumor mechanism of Diosgenin glucoside (DG) extracted from TTM is not clear.

Objective: This study aimed to investigate the anti-tumour effects of DG-induced osteosarcoma MG-63 cells and their molecular mechanism.

Methods: CCK-8 assay, HE staining, and flow cytometry were used to detect the effects of DG on the proliferation, apoptosis, and cell cycle of osteosarcoma cells. Wound healing and Transwell invasion assays were used to observe the effect of DG on the migration and invasion of osteosarcoma cells. The anti-tumour mechanism of DG on osteosarcoma cells was investigated by immunohistochemistry, Western blot, and RT-PCR.

Results: DG significantly inhibited osteosarcoma cell activity and proliferation, promoted apoptosis and blocked the G2 phase of the cell cycle. Both wound healing and Transwell invasion assays showed that DG inhibited osteosarcoma cell migration and invasion. Immunohistochemical and western blot results showed that DG inhibited the activation of PI3K/AKT/mTOR. We found that DG also significantly downregulated the expression of S6K1 and eIF4F, which might be associated with the inhibition of protein synthesis.

Conclusion: DG may inhibit proliferation, migration, invasion, and cell cycle G2 phase arrest of osteosarcoma MG-63 cells and promote apoptosis through the PI3K/AKT/mTOR signalling pathway.

Sobre autores

Siyuan Ruan

Department of Traumatic Orthopedics, Renmin Hospital, Hubei University of Medicine

Email: info@benthamscience.net

Liuwei Gu

Department of Traumatic Orthopedics, Renmin Hospital, Hubei University of Medicine

Email: info@benthamscience.net

Yuqi Wang

Department of Traumatic Orthopedics, Renmin Hospital, Hubei University of Medicine

Email: info@benthamscience.net

Xincheng Huang

Department of Traumatic Orthopedics, Renmin Hospital, Hubei University of Medicine

Email: info@benthamscience.net

Hong Cao

Department of Traumatic Orthopedics, Renmin Hospital, Hubei University of Medicine

Autor responsável pela correspondência
Email: info@benthamscience.net

Bibliografia

  1. Vijayamurugan, N.; Bakhshi, S. Review of management issues in relapsed osteosarcoma. Expert Rev. Anticancer Ther., 2014, 14(2), 151-161. doi: 10.1586/14737140.2014.863453 PMID: 24308680
  2. Yang, C.; Tian, Y.; Zhao, F.; Chen, Z.; Su, P.; Li, Y.; Qian, A. Bone microenvironment and osteosarcoma metastasis. Int. J. Mol. Sci., 2020, 21(19), 6985. doi: 10.3390/ijms21196985 PMID: 32977425
  3. Brown, H.K.; Tellez-Gabriel, M.; Heymann, D. Cancer stem cells in osteosarcoma. Cancer Lett., 2017, 386(17), 189-195. doi: 10.1016/j.canlet.2016.11.019 PMID: 27894960
  4. Zhang, J.; Yu, X.H.; Yan, Y.G.; Wang, C.; Wang, W.J. PI3K/Akt signaling in osteosarcoma. Clin. Chim. Acta, 2015, 44(4), 182-192.
  5. Chou, A.J.; Geller, D.S.; Gorlick, R. Therapy for osteosarcoma. Paediatr. Drugs, 2008, 10(5), 315-327. doi: 10.2165/00148581-200810050-00005 PMID: 18754698
  6. Gill, J.; Gorlick, R. Advancing therapy for osteosarcoma. Nat. Rev. Clin. Oncol., 2021, 18(10), 609-624. doi: 10.1038/s41571-021-00519-8 PMID: 34131316
  7. Qian, S.; Tong, S.; Wu, J.; Tian, L.; Qi, Z.; Chen, B.; Zhu, D.; Zhang, Y. Paris saponin VII extracted from Trillium tschonoskii induces autophagy and apoptosis in NSCLC cells. J. Ethnopharmacol., 2020, 248(14)112304 doi: 10.1016/j.jep.2019.112304 PMID: 31626908
  8. Tang, G.E.; Niu, Y.X.; Li, Y.; Wu, C.Y.; Wang, X.Y.; Zhang, J. Paris saponin VII enhanced the sensitivity of HepG2/ADR cells to ADR via modulation of PI3K/AKT/MAPK signaling pathway. Kaohsiung J. Med. Sci., 2020, 36(2), 98-106. doi: 10.1002/kjm2.12145 PMID: 31688993
  9. Lin, X.; Gajendran, B.; Varier, K.M.; Liu, W.; Song, J.; Rao, Q.; Wang, C.; Qiu, J.; Ni, W.; Qin, X.; Wen, M.; Liu, H.; Li, Y. Paris saponin VII induces apoptosis and cell cycle arrest in erythroleukemia cells by a mitochondrial membrane signaling pathway. Anticancer. Agents Med. Chem., 2021, 21(4), 498-507. doi: 10.2174/1871520620666200615134039 PMID: 32538736
  10. Hernández-Vázquez, J.M.V.; López-Muñoz, H.; Escobar-Sánchez, M.L.; Flores-Guzmán, F.; Weiss-Steider, B.; Hilario-Martínez, J.C.; Sandoval-Ramírez, J.; Fernández-Herrera, M.A.; Sánchez, L. Apoptotic, necrotic, and antiproliferative activity of diosgenin and diosgenin glycosides on cervical cancer cells. Eur. J. Pharmacol., 2020, 871(23)172942 doi: 10.1016/j.ejphar.2020.172942 PMID: 31972180
  11. Shen, Z.; Wang, J.; Ke, K.; Chen, R.; Zuo, A.; Zhang, R.; Wan, W.; Xie, X.; Li, X.; Song, N.; Fu, H.; Zhang, Z.; Cai, E.; Shen, J.; Zhang, Q.; Shi, X.; Polyphyllin, I. Polyphyllin I, a lethal partner of Palbociclib, suppresses non-small cell lung cancer through activation of p21/CDK2/Rb pathway in vitro and in vivo. Cell Cycle, 2021, 20(23), 2494-2506. doi: 10.1080/15384101.2021.1991121 PMID: 34658297
  12. Zhan, G.; Hu, J.; Xiao, B.; Wang, X.; Yang, Z.; Yang, G.; Lu, L. Trillin prevents proliferation and induces apoptosis through inhibiting STAT3 nuclear translocation in hepatoma carcinoma cells. Med. Oncol., 2020, 37(5), 44-49. doi: 10.1007/s12032-020-01369-7 PMID: 32270306
  13. Chen, X.B.; Wang, Z.L.; Yang, Q.Y.; Zhao, F.Y.; Qin, X.L.; Tang, X.E.; Du, J.L.; Chen, Z.H.; Zhang, K.; Huang, F.J. Diosgenin glucoside protects against spinal cord injury by regulating autophagy and alleviating apoptosis. Int. J. Mol. Sci., 2018, 19(8), 2274. doi: 10.3390/ijms19082274 PMID: 30072674
  14. Wu, Y.; Ye, F.; Lu, Y.; Yong, H.; Yin, R.; Chen, B.; Yong, Y. Diosgenin glucoside protects against myocardial injury in diabetic mice by inhibiting RIP140 signaling. Am. J. Transl. Res., 2018, 10(11), 3742-3749. PMID: 30662624
  15. Wang, B.; Li, J. Piceatannol suppresses the proliferation and induced apoptosis of osteosarcoma cells through PI3K/AKT/mTOR pathway. Cancer Manag. Res., 2020, 12(25), 2631-2640. doi: 10.2147/CMAR.S238173 PMID: 32368141
  16. Zheng, C.; Tang, F.; Min, L.; Hornicek, F.; Duan, Z.; Tu, C. PTEN in osteosarcoma: Recent advances and the therapeutic potential. Biochim. Biophys. Acta Rev. Cancer, 2020, 1874(2)188405 doi: 10.1016/j.bbcan.2020.188405 PMID: 32827577
  17. Hay, N.; Sonenberg, N. Upstream and downstream of mTOR. Genes Dev., 2004, 18(16), 1926-1945. doi: 10.1101/gad.1212704 PMID: 15314020
  18. Liu, P.; Gan, W.; Chin, Y.R.; Ogura, K.; Guo, J.; Zhang, J.; Wang, B.; Blenis, J.; Cantley, L.C.; Toker, A.; Su, B.; Wei, W. PtdIns(3,4,5) P 3-dependent activation of the mTORC2 kinase complex. Cancer Discov., 2015, 5(11), 1194-1209. doi: 10.1158/2159-8290.CD-15-0460 PMID: 26293922
  19. Lv, M.; Xu, Q.; Zhang, B.; Yang, Z.; Xie, J.; Guo, J.; He, F.; Wang, W. Imperatorin induces autophagy and G0/G1 phase arrest via PTEN-PI3K-AKT-mTOR/p21 signaling pathway in human osteosarcoma cells in vitro and in vivo. Cancer Cell Int., 2021, 21(1), 689-697. doi: 10.1186/s12935-021-02397-7 PMID: 34923996
  20. Teng, J.F.; Qin, D.L.; Mei, Q.B.; Qiu, W.Q.; Pan, R.; Xiong, R.; Zhao, Y.; Law, B.Y.K.; Wong, V.K.W.; Tang, Y.; Yu, C.L.; Zhang, F.; Wu, J.M.; Wu, A.G.; Polyphyllin, V.I. Polyphyllin VI, a saponin from Trillium tschonoskii Maxim. induces apoptotic and autophagic cell death via the ROS triggered mTOR signaling pathway in non-small cell lung cancer. Pharmacol. Res., 2019, 147(17)104396 doi: 10.1016/j.phrs.2019.104396 PMID: 31404628
  21. Guertin, D.A.; Sabatini, D.M. An expanding role for mTOR in cancer. Trends Mol. Med., 2005, 11(8), 353-361. doi: 10.1016/j.molmed.2005.06.007 PMID: 16002336
  22. Xu, K.; Liu, P.; Wei, W. mTOR signaling in tumorigenesis. Biochim. Biophys. Acta, 2014, 1846(2), 638-654. PMID: 25450580
  23. Litchfield, L.M.; Boehnke, K.; Brahmachary, M.; Mur, C.; Bi, C.; Stephens, J.R.; Sauder, J.M.; Gutiérrez, S.M.; McNulty, A.M.; Ye, X.S.; Wu, W.; Lallena, M.J.; Gong, X.; Merzoug, F.F.; Jansen, V.M.; Buchanan, S.G. Combined inhibition of PIM and CDK4/6 suppresses both mTOR signaling and Rb phosphorylation and potentiates PI3K inhibition in cancer cells. Oncotarget, 2020, 11(17), 1478-1492. doi: 10.18632/oncotarget.27539 PMID: 32391118
  24. Duan, Y.; Haybaeck, J.; Yang, Z. Therapeutic potential of PI3K/AKT/mTOR pathway in gastrointestinal stromal tumors: Rationale and progress. Cancers, 2020, 12(10), 2972. doi: 10.3390/cancers12102972 PMID: 33066449
  25. Merrick, W.C.; Pavitt, G.D. Protein synthesis initiation in eukaryotic cells. Cold Spring Harb. Perspect. Biol., 2018, 10(12)a033092 doi: 10.1101/cshperspect.a033092 PMID: 29735639
  26. Santini, E.; Klann, E. Reciprocal signaling between translational control pathways and synaptic proteins in autism spectrum disorders. Sci. Signal., 2014, 7(349), re10. doi: 10.1126/scisignal.2005832 PMID: 25351249
  27. Peter, D.; Igreja, C.; Weber, R.; Wohlbold, L.; Weiler, C.; Ebertsch, L.; Weichenrieder, O.; Izaurralde, E. Molecular architecture of 4E-BP translational inhibitors bound to eIF4E. Mol. Cell, 2015, 57(6), 1074-1087. doi: 10.1016/j.molcel.2015.01.017 PMID: 25702871
  28. Chawla, S.P.; Staddon, A.P.; Baker, L.H.; Schuetze, S.M.; Tolcher, A.W.; D'Amato, G.Z.; Blay, J.Y.; Mita, M.M.; Sankhala, K.K.; Berk, L.; Rivera, V.M.; Clackson, T.; Loewy, J.W.; Haluska, F.G.; Demetri, G.D. Phase II study of the mammalian target of rapamycin inhibitor ridaforolimus in patients with advanced bone and soft tissue sarcomas. J. Clin. Oncol., 2012, 30(1), 78-84. doi: 10.1200/JCO.2011.35.6329 PMID: 22067397

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