Salidroside suppresses the growth and invasion of human osteosarcoma cell lines MG63 and U2OS in vitro by inhibiting the JAK2/STAT3 signaling pathway

Huang,Lintuo; Huang,Zhengxiang; Lin,Wenjun; Wang,Lu; Zhu,Xiongbai; Chen,Xin; Yang,Shengwu; Lv,Chen

doi:10.3892/ijo.2019.4781

Salidroside suppresses the growth and invasion of human osteosarcoma cell lines MG63 and U2OS in vitro by inhibiting the JAK2/STAT3 signaling pathway

Authors:
- Lintuo Huang
- Zhengxiang Huang
- Wenjun Lin
- Lu Wang
- Xiongbai Zhu
- Xin Chen
- Shengwu Yang
- Chen Lv
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Affiliations: Department of Orthopedics, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
Published online on: April 10, 2019 https://doi.org/10.3892/ijo.2019.4781
Pages: 1969-1980
Copyright: © Huang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Previous research has reported that salidroside exerts antitumor properties on numerous types of tumor cells; however, its effect on osteosarcoma cells remains unknown. The present study aimed to investigate the effects of salidroside on the viability, apoptosis and invasion of osteosarcoma cells in vitro, and determine the underlying mechanism of action. The results of an MTT revealed that salidroside suppressed the viability of osteosarcoma cells (MG63 and U2OS cells) in a time‑ and concentration‑dependent manner. The results of cell morphological analysis (profile observations and Hoechst 33258 staining) and the detection of apoptosis by flow cytometry further indicated that the decrease in osteosarcoma cell viability induced by salidroside was associated with cell apoptosis. Western blot analysis not only confirmed these results but also suggested that salidroside induced the apoptosis of osteosarcoma cells by activating the caspase‑9‑dependent apoptotic pathway. In addition, we reported that salidroside induced G0/G1 phase arrest and suppressed the invasion of osteosarcoma cells, as measured by flow cytometric cell cycle analysis and a Transwell invasion assay, respectively. Western blot analysis confirmed the aforementioned results. Furthermore, our findings demonstrated that salidroside induced the apoptosis, G0/G1 phase arrest and suppressed the invasion of osteosarcoma cells by inhibiting the janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling pathway, as determined by western blot analysis. In summary, the findings of the present study suggested that salidroside may inhibit the progression of osteosarcoma by suppressing the growth and invasion of osteosarcoma cells. Furthermore, the investigations into the underlying mechanism demonstrated that salidroside exerted notable antitumor activity in osteosarcoma cells by inhibiting the JAK2/STAT3 signaling pathway.

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1	Ottaviani G and Jaffe N: The epidemiology of osteosarcoma. Cancer Treat Res. 152:3–13. 2009. View Article : Google Scholar
2	Lewis VO: What's new in musculoskeletal oncology. J Bone Joint Surg Am. 91:1546–1556. 2009. View Article : Google Scholar : PubMed/NCBI
3	Dominkus M, Darwish E and Funovics P: Reconstruction of the pelvis after resection of malignant bone tumours in children and adolescents. Recent Results Cancer Res. 179:85–111. 2009. View Article : Google Scholar : PubMed/NCBI
4	Fuchs B and Pritchard DJ: Etiology of osteosarcoma. Clin Orthop Relat Res. 397:40–52. 2002. View Article : Google Scholar
5	Picci P: Osteosarcoma (osteogenic sarcoma). Orphanet J Rare Dis. 2:62007. View Article : Google Scholar : PubMed/NCBI
6	Rosen G, Marcove RC, Caparros B, Nirenberg A, Kosloff C and Huvos AG: Primary osteogenic sarcoma: The rationale for preoperative chemotherapy and delayed surgery. Cancer. 43:2163–2177. 1979. View Article : Google Scholar : PubMed/NCBI
7	Kulchitsky VA, Potkin VI, Zubenko YS, Chernov AN, Talabaev MV, Demidchik YE, Petkevich SK, Kazbanov VV, Gurinovich TA, Roeva MO, et al: Cytotoxic effects of chemotherapeutic drugs and heterocyclic compounds at application on the cells of primary culture of neuroepithelium tumors. Med Chem. 8:22–32. 2012. View Article : Google Scholar : PubMed/NCBI
8	Tolonen A, Pakonen M, Hohtola A and Jalonen J: Phenylpropanoid glycosides from Rhodiola rosea. Chem Pharm Bull (Tokyo). 51:467–470. 2003. View Article : Google Scholar
9	Zhu Y, Zhang YJ, Liu WW, Shi AW and Gu N: Salidroside suppresses HUVECs cell injury induced by oxidative stress through activating the Nrf2 signaling pathway. Molecules. 21:212016. View Article : Google Scholar
10	Yang DW, Kang OH, Lee YS, Han SH, Lee SW, Cha SW, Seo YS, Mun SH, Gong R, Shin DW, et al: Anti-inflammatory effect of salidroside on phorbol-12-myristate-13-acetate plus A23187-mediated inflammation in HMC-1 cells. Int J Mol Med. 38:1864–1870. 2016. View Article : Google Scholar : PubMed/NCBI
11	Zhang L, Yu H, Zhao X, Lin X, Tan C, Cao G and Wang Z: Neuroprotective effects of salidroside against beta-amyloid-induced oxidative stress in SH-SY5Y human neuroblastoma cells. Neurochem Int. 57:547–555. 2010. View Article : Google Scholar : PubMed/NCBI
12	Zhang H, Shen WS, Gao CH, Deng LC and Shen D: Protective effects of salidroside on epirubicin-induced early left ventricular regional systolic dysfunction in patients with breast cancer. Drugs R D. 12:101–106. 2012. View Article : Google Scholar : PubMed/NCBI
13	Sun C, Wang Z, Zheng Q and Zhang H: Salidroside inhibits migration and invasion of human fibrosarcoma HT1080 cells. Phytomedicine : international journal of phytotherapy and phytopharmacology. 19:355–363. 2012. View Article : Google Scholar
14	Liu Z, Li X, Simoneau AR, Jafari M and Zi X: Rhodiola rosea extracts and salidroside decrease the growth of bladder cancer cell lines via inhibition of the mTOR pathway and induction of autophagy. Mol Carcinog. 51:257–267. 2012. View Article : Google Scholar
15	Wang J, Li JZ, Lu AX, Zhang KF and Li BJ: Anticancer effect of salidroside on A549 lung cancer cells through inhibition of oxidative stress and phospho-p38 expression. Oncol Lett. 7:1159–1164. 2014. View Article : Google Scholar : PubMed/NCBI
16	Zhao G, Shi A, Fan Z and Du Y: Salidroside inhibits the growth of human breast cancer in vitro and in vivo. Oncol Rep. 33:2553–2560. 2015. View Article : Google Scholar : PubMed/NCBI
17	Lv C, Huang Y, Liu ZX, Yu D and Bai ZM: Salidroside reduces renal cell carcinoma proliferation by inhibiting JAK2/STAT3 signaling. Cancer Biomark. 17:41–47. 2016. View Article : Google Scholar : PubMed/NCBI
18	Denizot F and Lang R: Rapid colorimetric assay for cell growth and survival. Modifications to the tetrazolium dye procedure giving improved sensitivity and reliability. J Immunol Methods. 89:271–277. 1986. View Article : Google Scholar : PubMed/NCBI
19	Faisham WI, Mat Saad AZ, Alsaigh LN, Nor Azman MZ, Kamarul Imran M, Biswal BM, Bhavaraju VM, Salzihan MS, Hasnan J, Ezane AM, et al: Prognostic factors and survival rate of osteosarcoma: A single-institution study. Asia Pac J Clin Oncol. 13:e104-e1102017. View Article : Google Scholar
20	Hu X, Lin S, Yu D, Qiu S, Zhang X and Mei R: A preliminary study: The anti-proliferation effect of salidroside on different human cancer cell lines. Cell Biol Toxicol. 26:499–507. 2010. View Article : Google Scholar : PubMed/NCBI
21	Guo Y, Zhao Y, Zheng C, Meng Y and Yang Y: Synthesis, biological activity of salidroside and its analogues. Chem Pharm Bull (Tokyo). 58:1627–1629. 2010. View Article : Google Scholar
22	Farzaei MH, Bahramsoltani R and Rahimi R: Phytochemicals as adjunctive with conventional anticancer therapies. Curr Pharm Des. 22:4201–4218. 2016. View Article : Google Scholar : PubMed/NCBI
23	Zhang L, Yu H, Sun Y, Lin X, Chen B, Tan C, Cao G and Wang Z: Protective effects of salidroside on hydrogen peroxide-induced apoptosis in SH-SY5Y human neuroblastoma cells. Eur J Pharmacol. 564:18–25. 2007. View Article : Google Scholar : PubMed/NCBI
24	Li H and Chen C: Inhibition of autophagy enhances synergistic effects of Salidroside and anti-tumor agents against colorectal cancer. BMC Complement Altern Med. 17:5382017. View Article : Google Scholar : PubMed/NCBI
25	Qi Z, Tang T, Sheng L, Ma Y, Liu Y, Yan L, Qi S, Ling L and Zhang Y: Salidroside inhibits the proliferation and migration of gastric cancer cells via suppression of Src-associated signaling pathway activation and heat shock protein 70 expression. Mol Med Rep. 18:147–156. 2018.PubMed/NCBI
26	Normile D: Cell proliferation. Common control for cancer, stem cells. Science. 298:18692002. View Article : Google Scholar : PubMed/NCBI
27	Hu X, Ma J, Vikash V, Li J, Wu D, Liu Y, Zhang J and Dong W: Thymoquinone augments cisplatin-induced apoptosis on esophageal carcinoma through mitigating the activation of JAK2/STAT3 pathway. Dig Dis Sci. 63:126–134. 2018. View Article : Google Scholar
28	Lv C, Hao Y, Han Y, Zhang W, Cong L, Shi Y and Tu G: Role and mechanism of microRNA-21 in H₂O₂-induced apoptosis in bone marrow mesenchymal stem cells. J Clin Neurosci. 27:154–160. 2016. View Article : Google Scholar : PubMed/NCBI
29	Sherr CJ: Cancer cell cycles. Science. 274:1672–1677. 1996. View Article : Google Scholar : PubMed/NCBI
30	Lin W, Zhu X, Yang S, Chen X, Wang L, Huang Z, Ding Y, Huang L and Lv C: MicroRNA-203 inhibits proliferation and invasion, and promotes apoptosis of osteosarcoma cells by targeting Runt-related transcription factor 2. Biomed Pharmacother. 91:1075–1084. 2017. View Article : Google Scholar : PubMed/NCBI
31	Hu X, Zhang X, Qiu S, Yu D and Lin S: Salidroside induces cell-cycle arrest and apoptosis in human breast cancer cells. Biochem Biophys Res Commun. 398:62–67. 2010. View Article : Google Scholar : PubMed/NCBI
32	Tesser-Gamba F, Lopes LJ, Petrilli AS and Toledo SR: MAPK7 gene controls proliferation, migration and cell invasion in osteo-sarcoma. Mol Carcinog. 55:1700–1713. 2016. View Article : Google Scholar
33	Yu C and Wang W: Relationship between P15 gene mutation and formation and metastasis of malignant osteosarcoma. Med Sci Monit. 22:656–661. 2016. View Article : Google Scholar : PubMed/NCBI
34	Cui Y, Zhu JJ, Ma CB, Cui K, Wang F, Ni SH and Zhang ZY: Genetic polymorphisms in MMP 2, 3 and 9 genes and the susceptibility of osteosarcoma in a Chinese Han population. Biomarkers. 21:160–163. 2016. View Article : Google Scholar : PubMed/NCBI
35	Lv C, Yang S, Chen X, Zhu X, Lin W, Wang L, Huang Z, Wang M and Tu G: MicroRNA-21 promotes bone mesenchymal stem cells migration in vitro by activating PI3K/Akt/MMPs pathway. J Clin Neurosci. 46:156–162. 2017. View Article : Google Scholar : PubMed/NCBI
36	Fan XJ, Wang Y, Wang L and Zhu M: Salidroside induces apoptosis and autophagy in human colorectal cancer cells through inhibition of PI3K/Akt/mTOR pathway. Oncol Rep. 36:3559–3567. 2016. View Article : Google Scholar : PubMed/NCBI
37	Kang DY, Sp N, Kim DH, Joung YH, Lee HG, Park YM and Yang YM: Salidroside inhibits migration, invasion and angiogenesis of MDA-MB 231 TNBC cells by regulating EGFR/Jak2/STAT3 signaling via MMP2. Int J Oncol. 53:877–885. 2018.PubMed/NCBI
38	Bill MA, Nicholas C, Mace TA, Etter JP, Li C, Schwartz EB, Fuchs JR, Young GS, Lin L, Lin J, et al: Structurally modified curcumin analogs inhibit STAT3 phosphorylation and promote apoptosis of human renal cell carcinoma and melanoma cell lines. PLoS One. 7:e407242012. View Article : Google Scholar : PubMed/NCBI
39	Sun KX, Xia HW and Xia RL: Anticancer effect of salidroside on colon cancer through inhibiting JAK2/STAT3 signaling pathway. Int J Clin Exp Pathol. 8:615–621. 2015.PubMed/NCBI
40	Mahmoud AM and Abd El-Twab SM: Caffeic acid phenethyl ester protects the brain against hexavalent chromium toxicity by enhancing endogenous antioxidants and modulating the JAK/STAT signaling pathway. Biomed Pharmacother. 91:303–311. 2017. View Article : Google Scholar : PubMed/NCBI
41	Tian Y, Zhang W, Xia D, Modi P, Liang D and Wei M: Postconditioning inhibits myocardial apoptosis during prolonged reperfusion via a JAK2 STAT3-Bcl-2 pathway. J Biomed Sci. 18:532011. View Article : Google Scholar
42	Wu KJ, Huang JM, Zhong HJ, Dong ZZ, Vellaisamy K, Lu JJ, Chen XP, Chiu P, Kwong DWJ, Han QB, et al: A natural product-like JAK2/STAT3 inhibitor induces apoptosis of malignant melanoma cells. PLoS One. 12:e01771232017. View Article : Google Scholar : PubMed/NCBI
43	Shokoohinia Y, Jafari F, Mohammadi Z, Bazvandi L, Hosseinzadeh L, Chow N, Bhattacharyya P, Farzaei MH, Farooqi AA, Nabavi SM, et al: Potential anticancer properties of osthol: A comprehensive mechanistic review. Nutrients. 10:102018. View Article : Google Scholar
44	Shi X, Zhao W, Yang Y, Wu S and Lv B: Salidroside could enhance the cytotoxic effect of L-OHP on colorectal cancer cells. Mol Med Rep. 17:51–58. 2018.