Salinomycin causes migration and invasion of human fibrosarcoma cells by inducing MMP-2 expression via PI3-kinase, ERK-1/2 and p38 kinase pathways

Yu,Seon-Mi; Kim,Song  Ja

doi:10.3892/ijo.2016.3448

Salinomycin causes migration and invasion of human fibrosarcoma cells by inducing MMP-2 expression via PI3-kinase, ERK-1/2 and p38 kinase pathways

Authors:
- Seon-Mi Yu
- Song Ja Kim
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Affiliations: Department of Biological Sciences, College of Natural Sciences, Kongju National University, Gongju, Republic of Korea
Published online on: March 22, 2016 https://doi.org/10.3892/ijo.2016.3448
Pages: 2686-2692

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Abstract

Salinomycin (SAL) is a polyether ionophore antibiotic that has recently been shown to regulate a variety of cellular responses in various human cancer cells. However, the effects of SAL on metastatic capacity of HT1080 human fibrosarcoma cells have not been elucidated. We investigated the effect of SAL on migration and invasion, with emphasis on the expression and activation of matrix metalloproteinase (MMP)-2 in HT1080 human fibrosarcoma cells. Treatment of SAL promoted the expression and activation of MMP-2 in a dose- and time-dependent manner, as detected by western blot analysis, gelatin zymography, and real-time polymerase chain reaction. SAL also increased metastatic capacities, as determined by an increase in the migration and invasion of cells using the wound healing assay and the invasion assay, respectively. To confirm the detailed molecular mechanisms of these effects, we measured the activation of phosphoinositide 3 kinase (PI3-kinase) and mitogen-activated protein kinase (MAPK)s (ERK-1/2 and p38 kinase), as detected by the phosphorylated proteins through western blot analysis. SAL treatment increased the phosphorylation of Akt and MAPKs. Inhibition of PI3-kinase, ERK-1/2, and p38 kinase with LY294002, PD98059, and SB203580, respectively, in the presence of SAL suppressed the metastatic capacity by reducing MMP-2 expression, as determined by gelatin zymography. Our results indicate that the PI3-kinase and MAPK signaling pathways are involved in migration and invasion of HT1080 through induction of MMP-2 expression and activation. In conclusion, SAL significantly increases the metastatic capacity of HT1080 cells by inducing MMP-2 expression via PI3-kinase and MAPK pathways. Our results suggest that SAL may be a potential agent for the study of cancer metastatic capacities.

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1	Franco R, Zappavigna S, Gigantino V, Luce A, Cantile M, Cerrone M, Facchini G, Perdonà S, Pignata S, Di Lorenzo G, et al: Urotensin II receptor determines prognosis of bladder cancer regulating cell motility/invasion. J Exp Clin Cancer Res. 33:482014. View Article : Google Scholar : PubMed/NCBI
2	Molina JR, Yang P, Cassivi SD, Schild SE and Adjei AA: Non-small cell lung cancer: Epidemiology, risk factors, treatment, and survivorship. Mayo Clin Proc. 83:584–594. 2008. View Article : Google Scholar : PubMed/NCBI
3	Fisher KE, Pop A, Koh W, Anthis NJ, Saunders WB and Davis GE: Tumor cell invasion of collagen matrices requires coordinate lipid agonist-induced G-protein and membrane-type matrix metalloproteinase-1-dependent signaling. Mol Cancer. 5:692006. View Article : Google Scholar : PubMed/NCBI
4	Kessenbrock K, Plaks V and Werb Z: Matrix metalloproteinases: Regulators of the tumor microenvironment. Cell. 141:52–67. 2010. View Article : Google Scholar : PubMed/NCBI
5	Stamenkovic I: Matrix metalloproteinases in tumor invasion and metastasis. Semin Cancer Biol. 10:415–433. 2000. View Article : Google Scholar
6	Forget MA, Desrosiers RR and Béliveau R: Physiological roles of matrix metalloproteinases: Implications for tumor growth and metastasis. Can J Physiol Pharmacol. 77:465–480. 1999. View Article : Google Scholar : PubMed/NCBI
7	Curran S, Dundas SR, Buxton J, Leeman MF, Ramsay R and Murray GI: Matrix metalloproteinase/tissue inhibitors of matrix metalloproteinase phenotype identifies poor prognosis colorectal cancers. Clin Cancer Res. 10:8229–8234. 2004. View Article : Google Scholar : PubMed/NCBI
8	Gomez DE, Alonso DF, Yoshiji H and Thorgeirsson UP: Tissue inhibitors of metalloproteinases: Structure, regulation and biological functions. Eur J Cell Biol. 74:111–122. 1997.PubMed/NCBI
9	Mook OR, Frederiks WM and Van Noorden CJ: The role of gelatinases in colorectal cancer progression and metastasis. Biochim Biophys Acta. 1705:69–89. 2004.PubMed/NCBI
10	Koshiba T, Hosotani R, Wada M, Miyamoto Y, Fujimoto K, Lee JU, Doi R, Arii S and Imamura M: Involvement of matrix metalloproteinase-2 activity in invasion and metastasis of pancreatic carcinoma. Cancer. 82:642–650. 1998. View Article : Google Scholar : PubMed/NCBI
11	Guo CB, Wang S, Deng C, Zhang DL, Wang FL and Jin XQ: Relationship between matrix metalloproteinase 2 and lung cancer progression. Mol Diagn Ther. 11:183–192. 2007. View Article : Google Scholar : PubMed/NCBI
12	Papadopoulou S, Scorilas A, Arnogianaki N, Papapanayiotou B, Tzimogiani A, Agnantis N and Talieri M: Expression of gelatinase-A (MMP-2) in human colon cancer and normal colon mucosa. Tumour Biol. 22:383–389. 2001. View Article : Google Scholar
13	Björklund M and Koivunen E: Gelatinase-mediated migration and invasion of cancer cells. Biochim Biophys Acta. 1755:37–69. 2005.PubMed/NCBI
14	Engelman JA, Luo J and Cantley LC: The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism. Nat Rev Genet. 7:606–619. 2006. View Article : Google Scholar : PubMed/NCBI
15	García Z, Kumar A, Marqués M, Cortés I and Carrera AC: Phosphoinositide 3-kinase controls early and late events in mammalian cell division. EMBO J. 25:655–661. 2006. View Article : Google Scholar : PubMed/NCBI
16	Naujokat C, Fuchs D and Opelz G: Salinomycin in cancer: A new mission for an old agent. Mol Med Rep. 3:555–559. 2010. View Article : Google Scholar
17	Jayapalan JJ, Ng KL, Razack AH and Hashim OH: Identification of potential complementary serum biomarkers to differentiate prostate cancer from benign prostatic hyperplasia using gel- and lectin-based proteomics analyses. Electrophoresis. 33:1855–1862. 2012. View Article : Google Scholar : PubMed/NCBI
18	Herr MJ, Kotha J, Hagedorn N, Smith B and Jennings LK: Tetraspanin CD9 promotes the invasive phenotype of human fibrosarcoma cells via upregulation of matrix metalloproteinase-9. PLoS One. 8:e677662013. View Article : Google Scholar : PubMed/NCBI
19	Nelson AR, Fingleton B, Rothenberg ML and Matrisian LM: Matrix metalloproteinases: Biologic activity and clinical implications. J Clin Oncol. 18:1135–1149. 2000.PubMed/NCBI
20	Chung TW, Moon SK, Lee YC, Kim JG, Ko JH and Kim CH: Enhanced expression of matrix metalloproteinase-9 by hepatitis B virus infection in liver cells. Arch Biochem Biophys. 408:147–154. 2002. View Article : Google Scholar : PubMed/NCBI
21	Basset P, Okada A, Chenard MP, Kannan R, Stoll I, Anglard P, Bellocq JP and Rio MC: Matrix metalloproteinases as stromal effectors of human carcinoma progression: Therapeutic implications. Matrix Biol. 15:535–541. 1997. View Article : Google Scholar : PubMed/NCBI
22	Yamada KM, Kennedy DW, Yamada SS, Gralnick H, Chen WT and Akiyama SK: Monoclonal antibody and synthetic peptide inhibitors of human tumor cell migration. Cancer Res. 50:4485–4496. 1990.PubMed/NCBI
23	Watanabe H, Carmi P, Hogan V, Raz T, Silletti S, Nabi IR and Raz A: Purification of human tumor cell autocrine motility factor and molecular cloning of its receptor. J Biol Chem. 266:13442–13448. 1991.PubMed/NCBI
24	Mukaida N, Gussella GL, Kasahara T, Ko Y, Zachariae CO, Kawai T and Matsushima K: Molecular analysis of the inhibition of interleukin-8 production by dexamethasone in a human fibrosarcoma cell line. Immunology. 75:674–679. 1992.PubMed/NCBI
25	Stetler-Stevenson WG: Type IV collagenases in tumor invasion and metastasis. Cancer Metastasis Rev. 9:289–303. 1990. View Article : Google Scholar : PubMed/NCBI
26	Kim S, Ding W, Zhang L, Tian W and Chen S: Clinical response to sunitinib as a multitargeted tyrosine-kinase inhibitor (TKI) in solid cancers: A review of clinical trials. Onco Targets Ther. 7:719–728. 2014.PubMed/NCBI
27	Antoszczak M, Popiel K, Stefańska J, Wietrzyk J, Maj E, Janczak J, Michalska G, Brzezinski B and Huczyński A: Synthesis, cytotoxicity and antibacterial activity of new esters of polyether antibiotic - salinomycin. Eur J Med Chem. 76:435–444. 2014. View Article : Google Scholar : PubMed/NCBI
28	Ramsay AG, Marshall JF and Hart IR: Integrin trafficking and its role in cancer metastasis. Cancer Metastasis Rev. 26:567–578. 2007. View Article : Google Scholar : PubMed/NCBI
29	Luo BH, Carman CV and Springer TA: Structural basis of integrin regulation and signaling. Annu Rev Immunol. 25:619–647. 2007. View Article : Google Scholar : PubMed/NCBI
30	Vivanco I and Sawyers CL: The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nat Rev Cancer. 2:489–501. 2002. View Article : Google Scholar : PubMed/NCBI
31	Bellacosa A, Kumar CC, Di Cristofano A and Testa JR: Activation of AKT kinases in cancer: Implications for therapeutic targeting. Adv Cancer Res. 94:29–86. 2005. View Article : Google Scholar : PubMed/NCBI
32	Guo J, Jie W, Shen Z, Li M, Lan Y, Kong Y, Guo S, Li T and Zheng S: SCF increases cardiac stem cell migration through PI3K/AKT and MMP-2/-9 signaling. Int J Mol Med. 34:112–118. 2014.PubMed/NCBI
33	Hou J, Wang L, Jiang J, Zhou C, Guo T, Zheng S and Wang T: Cardiac stem cells and their roles in myocardial infarction. Stem Cell Rev. 9:326–338. 2013. View Article : Google Scholar
34	Theodosiou A and Ashworth A: MAP kinase phosphatases. Genome Biol. 3:Reviews3009. 2002. View Article : Google Scholar : PubMed/NCBI