Celastrol negatively regulates cell invasion and migration ability of human osteosarcoma via downregulation of the PI3K/Akt/NF-κB signaling pathway in vitro

Yu,Xiaolong; Wang,Qiang; Zhou,Xin; Fu,Changlin; Cheng,Ming; Guo,Runsheng; Liu,Hucheng; Zhang,Bin; Dai,Min

doi:10.3892/ol.2016.5049

November-2016 Volume 12 Issue 5

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November-2016 Volume 12 Issue 5

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Article

Celastrol negatively regulates cell invasion and migration ability of human osteosarcoma via downregulation of the PI3K/Akt/NF-κB signaling pathway in vitro

Authors:
- Xiaolong Yu
- Qiang Wang
- Xin Zhou
- Changlin Fu
- Ming Cheng
- Runsheng Guo
- Hucheng Liu
- Bin Zhang
- Min Dai
View Affiliations / Copyright

Affiliations: Department of Orthopedics, The First Affiliated Hospital of Nanchang University, Artificial Joints Engineering and Technology Research Center of Jiangxi Province, Nanchang, Jiangxi 330006, P.R. China, Multidisciplinary Therapy Center of Musculoskeletal Tumor, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
Pages: 3423-3428
|
Published online on: August 26, 2016

https://doi.org/10.3892/ol.2016.5049
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Abstract

Osteosarcoma (OS) is a primary malignant tumor of the bone, with a tendency to metastasize early. Despite the advances in treatment options, more than 30% of patients develop distant metastases, and the prognosis of these patients with metastases is extremely poor. Celastrol has been demonstrated to manifest multiple pharmacological activities, including induction of apoptosis in numerous types of cancer cell lines. Our previous studies have also suggested that Celastrol is capable of inducing apoptosis of human osteosarcoma cells via the mitochondrial‑dependent pathway. The purpose of this study was to investigate the effects of Celastrol on the migration and invasion of human osteosarcoma U‑2OS cells in vitro. Cell migration and invasion were investigated using wound healing and Boyden chamber Transwell assays. We observed that Celastrol suppressed cell invasion and migration in human osteosarcoma U‑2OS cells. Furthermore, protein expression levels of phosphorylated phosphatidylinositol 3-kinase (PI3K), Akt, inhibitor of κB kinase α/β, inhibitor of κB α, nuclear factor‑κB (NF‑κB subunit p65) and matrix metalloproteinase (MMP)‑2 and ‑9 were measured by western blot analysis. We observed that the PI3K/Akt/NF‑κB signaling pathway was inhibited following Celastrol treatment. In addition, the expression levels of MMP‑2 and ‑9 proteins were also reduced significantly following Celastrol treatment. Therefore, we confirmed that Celastrol suppressed osteosarcoma U‑2OS cell metastasis via downregulation of the PI3K/Akt/NF-κB signaling pathway in vitro.

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1	Damron TA, Ward WG and Stewart A: Osteosarcoma, chondrosarcoma, and Ewing's sarcoma: National Cancer Data Base Report. Clin Orthop Relat Res. 459:40–47. 2007. View Article : Google Scholar : PubMed/NCBI
2	Poletajew S, Fus L and Wasiutyński A: Current concepts on pathogenesis and biology of metastatic osteosarcoma tumors. Ortop Traumatol Rehabil. 13:537–545. 2011.(In English and Polish). View Article : Google Scholar : PubMed/NCBI
3	Gill J, Ahluwalia MK, Geller D and Gorlick R: New targets and approaches in osteosarcoma. Pharmacol Ther. 137:89–99. 2013. View Article : Google Scholar : PubMed/NCBI
4	Guise TA, O'Keefe R, Randall RL and Terek RM: Molecular biology and therapeutics in musculoskeletal oncology. J Bone Joint Surg Am. 91:724–732. 2009. View Article : Google Scholar : PubMed/NCBI
5	Salah S and Toubasi S: Factors predicting survival following complete surgical remission of pulmonary metastasis in osteosarcoma. Mol Clin Oncol. 3:157–162. 2015.PubMed/NCBI
6	Stefanatos RK and Vidal M: Tumor invasion and metastasis in Drosophila: a bold past, a bright future. J Genet Genomics. 38:431–438. 2011. View Article : Google Scholar : PubMed/NCBI
7	Mareel M, Oliveira MJ and Madani I: Cancer invasion and metastasis: interacting ecosystems. Virchows Arch. 454:599–622. 2009. View Article : Google Scholar : PubMed/NCBI
8	Shen A, Zhang Y, Yang H, Xu R and Huang G: Overexpression of ZEB1 relates to metastasis and invasion in osteosarcoma. J Surg Oncol. 105:830–834. 2012. View Article : Google Scholar : PubMed/NCBI
9	Watanabe H: Extracellular matrix-regulation of cancer invasion and metastasis. Gan To Kagaku Ryoho. 37:2058–2061. 2010.(In Japanese). PubMed/NCBI
10	Lin YM, Chang ZL, Liao YY, Chou MC and Tang CH: IL-6 promotes ICAM-1 expression and cell motility in human osteosarcoma. Cancer Lett. 328:135–143. 2013. View Article : Google Scholar : PubMed/NCBI
11	van Zijl F, Krupitza G and Mikulits W: Initial steps of metastasis: cell invasion and endothelial transmigration. Mutat Res. 728:23–34. 2011. View Article : Google Scholar : PubMed/NCBI
12	Willis AL, Sabeh F, Li XY and Weiss SJ: Extracellular matrix determinants and the regulation of cancer cell invasion stratagems. J Microsc. 251:250–260. 2013. View Article : Google Scholar : PubMed/NCBI
13	Polette M, Nawrocki-Raby B, Gilles C, Clavel C and Birembaut P: Tumour invasion and matrix metalloproteinases. Crit Rev Oncol Hematol. 49:179–186. 2004. View Article : Google Scholar : PubMed/NCBI
14	Moss LA Shuman, Jensen-Taubman S and Stetler-Stevenson WG: Matrix metalloproteinases: changing roles in tumor progression and metastasis. Am J Pathol. 181:1895–1899. 2012. View Article : Google Scholar : PubMed/NCBI
15	Lynch CC: Matrix metalloproteinases as master regulators of the vicious cycle of bone metastasis. Bone. 48:44–53. 2011. View Article : Google Scholar : PubMed/NCBI
16	Halbersztadt A, Haloń A, Pajak J, Robaczyński J, Rabczynski J and St Gabryś M: The role of matrix metalloproteinases in tumor invasion and metastasis. Ginekol Pol. 77:63–71. 2006.(In Polish). PubMed/NCBI
17	Khasigov PZ, Podobed OV, Gracheva TS, Salbiev KD, Grachev SV and Berezov TT: Role of matrix metalloproteinases and their inhibitors in tumor invasion and metastasis. Biochemistry (Mosc). 68:711–717. 2003. View Article : Google Scholar : PubMed/NCBI
18	Deryugina EI and Quigley JP: Matrix metalloproteinases and tumor metastasis. Cancerr Metastasis Rev. 25:9–34. 2006. View Article : Google Scholar
19	Korpi JT, Hagström J, Lehtonen N, Parkkinen J, Sorsa T, Salo T and Laitinen M: Expression of matrix metalloproteinases-2, −8, −13, −26, and tissue inhibitors of metalloproteinase-1 in human osteosarcoma. Surg Oncol. 20:e18–e22. 2011. View Article : Google Scholar : PubMed/NCBI
20	Bjørnland K, Flatmark K, Pettersen S, Aaasen AO, Fodstad O and Maelandsmo GM: Matrix metalloproteinases participate in osteosarcoma invasion. J Surg Res. 127:151–156. 2005. View Article : Google Scholar : PubMed/NCBI
21	Loukopoulos P, O'Brien T, Ghoddusi M, Mungall BA and Robinson WF: Characterisation of three novel canine osteosarcoma cell lines producing high levels of matrix metalloproteinases. Res Vet Sci. 77:131–141. 2004. View Article : Google Scholar : PubMed/NCBI
22	Felx M, Guyot MC, Isler M, Turcotte RE, Doyon J, Khatib AM, Leclerc S, Moreau A and Moldovan F: Endothelin-1 (ET-1) promotes MMP-2 and MMP-9 induction involving the transcription factor NF-kappaB in human osteosarcoma. Clin Sci (Lond). 110:645–654. 2006. View Article : Google Scholar : PubMed/NCBI
23	Zhang XX, Fu Z, Zhang Z, Miao C, Xu P, Wang T, Yang L and Cheng S: Microcystin-LR promotes melanoma cell invasion and enhances matrix metalloproteinase-2/-9 expression mediated by NF-κB activation. Environ Sci Technol. 46:11319–11326. 2012. View Article : Google Scholar : PubMed/NCBI
24	Ahmad A, Biersack B, Li Y, Kong D, Bao B, Schobert R, Padhye SB and Sarkar FH: Targeted regulation of PI3K/Akt/mTOR/NF-κB signaling by indole compounds and their derivatives: mechanistic details and biological implications for cancer therapy. Anticancer Agents Med Chem. 13:1002–1013. 2013. View Article : Google Scholar : PubMed/NCBI
25	Kuan YH, Huang FM, Li YC and Chang YC: Proinflammatory activation of macrophages by bisphenol A-glycidyl-methacrylate involved NF-κB activation via PI3K/Akt pathway. Food Chem Toxicol. 50:4003–4009. 2012. View Article : Google Scholar : PubMed/NCBI
26	Shrivastava S, Jeengar MK, Reddy VS, Reddy GB and Naidu VG: Anticancer effect of celastrol on human triple negative breast cancer: possible involvement of oxidative stress, mitochondrial dysfunction, apoptosis and PI3K/Akt pathways. Exp Mol Pathol. 98:313–327. 2015. View Article : Google Scholar : PubMed/NCBI
27	Li PP, He W, Yuan PF, Song SS, Lu JT and Wei W: Celastrol induces mitochondria-mediated apoptosis in hepatocellular carcinoma Bel-7402 cells. Am J Chin Med. 43:137–148. 2015. View Article : Google Scholar : PubMed/NCBI
28	Mi C, Shi H, Ma J, Han LZ, Lee JJ and Jin X: Celastrol induces the apoptosis of breast cancer cells and inhibits their invasion via downregulation of MMP-9. Oncol Rep. 32:2527–2532. 2014.PubMed/NCBI
29	Zhao X, Gao S, Ren H, Huang H, Ji W and Hao J: Inhibition of autophagy strengthens celastrol-induced apoptosis in human pancreatic cancer in vitro and in vivo models. Curr Mol Med. 14:555–563. 2014. View Article : Google Scholar : PubMed/NCBI
30	Sampo M, Koivikko M, Taskinen M, Kallio P, Kivioja A, Tarkkanen M and Böhling T: Incidence, epidemiology and treatment results of osteosarcoma in Finland - a nationwide population-based study. Acta Oncol. 50:1206–1214. 2011. View Article : Google Scholar : PubMed/NCBI
31	Mirabello L, Troisi RJ and Savage SA: International osteosarcoma incidence patterns in children and adolescents, middle ages and elderly persons. Int J Cancer. 125:229–234. 2009. View Article : Google Scholar : PubMed/NCBI
32	Dai X, Ma W, He X and Jha RK: Review of therapeutic strategies for osteosarcoma, chondrosarcoma, and Ewing's sarcoma. Med Sci Monit. 17:RA177–RA190. 2011. View Article : Google Scholar : PubMed/NCBI
33	Ando K, Heymann MF, Stresing V, Mori K, Rédini F and Heymann D: Current therapeutic strategies and novel approaches in osteosarcoma. Cancers (Basel). 5:591–616. 2013. View Article : Google Scholar : PubMed/NCBI
34	Lamoureux F, Trichet V, Chipoy C, Blanchard F, Gouin F and Redini F: Recent advances in the management of osteosarcoma and forthcoming therapeutic strategies. Expert Rev Anticancer Ther. 7:169–181. 2007. View Article : Google Scholar : PubMed/NCBI
35	Li Y, Liao Q, Li K, Zhong D, Weng X and Mi M: Knockdown of endothelin A receptor expression inhibits osteosarcoma pulmonary metastasis in an orthotopic xenograft mouse model. Mol Med Rep. 5:1391–1395. 2012.PubMed/NCBI
36	Kato H, Wakabayashi H, Naito Y, Kato S, Nakagawa T, Matsumine A and Sudo A: Anti-tumor necrosis factor therapy inhibits lung metastasis in an osteosarcoma cell line. Oncology. 88:139–146. 2015.PubMed/NCBI
37	Daw NC, Chou AJ, Jaffe N, Rao BN, Billups CA, Rodriguez-Galindo C, Meyers PA and Huh WW: Recurrent osteosarcoma with a single pulmonary metastasis: a multi-institutional review. Br J Cancer. 112:278–282. 2015. View Article : Google Scholar : PubMed/NCBI
38	Hou CH, Lin FL, Tong KB, Hou SM and Liu JF: Transforming growth factor alpha promotes osteosarcoma metastasis by ICAM-1 and PI3K/Akt signaling pathway. Biochem Pharmacol. 89:453–463. 2014. View Article : Google Scholar : PubMed/NCBI
39	Zhang J, Yu XH, Yan YG, Wang C and Wang WJ: PI3K/Akt signaling in osteosarcoma. Clin Chim Acta. 444:182–192. 2015. View Article : Google Scholar : PubMed/NCBI
40	Allison AC, Cacabelos R, Lombardi VR, Alvarez XA and Vigo C: Celastrol, a potent antioxidant and anti-inflammatory drug, as a possible treatment for Alzheimer's disease. Prog Neuropsychopharmacol Biol Psychiatry. 25:1341–1357. 2001. View Article : Google Scholar : PubMed/NCBI
41	Cleren C, Calingasan NY, Chen J and Beal MF: Celastrol protects against MPTP- and 3-nitropropionic acid induced neurotoxicity. J Neurochem. 94:995–1004. 2005. View Article : Google Scholar : PubMed/NCBI
42	Jung HW, Chung YS, Kim YS and Park YK: Celastrol inhibits production of nitric oxide and proinflammatory cytokines through MAPK signal transduction and NF-kappaB in LPS-stimulated BV-2 microglial cells. Exp Mol Med. 39:715–721. 2007. View Article : Google Scholar : PubMed/NCBI
43	Yu X, Zhou X, Fu C, Wang Q, Nie T, Zou F, Guo R, Liu H, Zhang B and Dai M: Celastrol induces apoptosis of human osteosarcoma cells via the mitochondrial apoptotic pathway. Oncol Rep. 34:1129–1136. 2015.PubMed/NCBI