Potential therapy with the inhibitor of TGF-β receptors LY2109761 for oral squamous cell carcinoma
DOI:
https://doi.org/10.33448/rsd-v10i9.18396Keywords:
Cell migration; Cytoskeleton; LY2109761; Oral squamous cell carcinoma; SCC-4.Abstract
One way of trying to control oral squamous cell carcinoma is to invest in new therapies focused on the molecular biology of receptors and their intracellular signaling pathways. This study aimed to evaluate the effect of LY2109761 (an inhibitor of TGF-β receptors) on cell migration in oral squamous cell carcinoma in vitro. Actin cytoskeleton of SCC-4 cells control and LY2109761 (1, 5 and 10 μM) treated on three-dimensional Matrigel were analysed by using confocal laser microscopy. Control and LY2109761 (1, 5 and 10 μM) treated cells that migrated through the membrane of three-dimensional cell migration assays were counted, significance was p<0.05. Control cells were seen with voluminous cytoplasm, cell cortex preserved and actin cytoskeleton well developed with well distributed actin filaments. Regardless of concentration, cells treated showed: rounded morphology and small size, scanty cytoplasm, cortical F-actin less clear that the control cells, and disruption of actin filaments. The migratory cells were inhibited by treatment with LY2109761 [F (3, 11) = 3742, p<0.0001], in a dose-dependent manner. These results suggest that LY2109761 exerts an inhibitory effect on the actin cytoskeleton and cell migration on SCC-4 cells, therefore, it is a promising therapeutic option for oral squamous cell carcinoma.
References
Albini, A., & Noonan, D. M. (2010). The 'chemoinvasion' assay, 25 years and still going strong: the use of reconstituted basement membranes to study cell invasion and angiogenesis. Curr Opin Cell Biol, 22(5), 677-689. https://doi.org/10.1016/j.ceb.2010.08.017
Blume-Jensen, P., & Hunter, T. (2001). Oncogenic kinase signalling. Nature, 411(6835), 355-365. https://doi.org/10.1038/35077225
Bu, J. Q., & Chen, F. (2017). TGF-β1 promotes cells invasion and migration by inducing epithelial mesenchymal transformation in oral squamous cell carcinoma. Eur Rev Med Pharmacol Sci, 21(9), 2137-2144.
Capece, D., Verzella, D., Tessitore, A., Alesse, E., Capalbo, C., & Zazzeroni, F. (2017). Cancer secretome and inflammation: The bright and the dark sides of NF-κB. Semin Cell Dev Biol. https://doi.org/10.1016/j.semcdb.2017.08.004
Chen, Y., Di, C., Zhang, X., Wang, J., Wang, F., Yan, J. F., Zhang, H. (2020). Transforming growth factor β signaling pathway: A promising therapeutic target for cancer. J Cell Physiol, 235(3), 1903-1914. https://doi.org/10.1002/jcp.29108
Clark, A. G., & Vignjevic, D. M. (2015). Modes of cancer cell invasion and the role of the microenvironment. Curr Opin Cell Biol, 36, 13-22. https://doi.org/10.1016/j.ceb.2015.06.004
Connolly, E. C., Freimuth, J., & Akhurst, R. J. (2012). Complexities of TGF-β targeted cancer therapy. Int J Biol Sci, 8(7), 964-978. https://doi.org/10.7150/ijbs.4564
Drabsch, Y., & ten Dijke, P. (2012). TGF-β signalling and its role in cancer progression and metastasis. Cancer Metastasis Rev, 31(3-4), 553-568. https://doi.org/10.1007/s10555-012-9375-7
Howell, G. M., & Grandis, J. R. (2005). Molecular mediators of metastasis in head and neck squamous cell carcinoma. Head Neck, 27(8), 710-717. https://doi.org/10.1002/hed.20222
Hunter, T. (2014). The genesis of tyrosine phosphorylation. Cold Spring Harb Perspect Biol, 6(5), a020644. https://doi.org/10.1101/cshperspect.a020644
Joseph, J. V., Balasubramaniyan, V., Walenkamp, A., & Kruyt, F. A. (2013). TGF-β as a therapeutic target in high grade gliomas - promises and challenges. Biochem Pharmacol, 85(4), 478-485. https://doi.org/10.1016/j.bcp.2012.11.005
Krakhmal, N. V., Zavyalova, M. V., Denisov, E. V., Vtorushin, S. V., & Perelmuter, V. M. (2015). Cancer Invasion: Patterns and Mechanisms. Acta Naturae, 7(2), 17-28.
Kramer, N., Walzl, A., Unger, C., Rosner, M., Krupitza, G., Hengstschläger, M., & Dolznig, H. (2013). In vitro cell migration and invasion assays. Mutat Res, 752(1), 10-24. https://doi.org/10.1016/j.mrrev.2012.08.001
Lehtimäki, J., Hakala, M., & Lappalainen, P. (2016). Actin Filament Structures in Migrating Cells. Handb Exp Pharmacol. https://doi.org/10.1007/164_2016_28
Lemmon, M. A., & Schlessinger, J. (2010). Cell signaling by receptor tyrosine kinases. Cell, 141(7), 1117-1134. https://doi.org/10.1016/j.cell.2010.06.011
Li, H. Y., McMillen, W. T., Heap, C. R., McCann, D. J., Yan, L., Campbell, R. M., . . . Sawyer, J. S. (2008). Optimization of a dihydropyrrolopyrazole series of transforming growth factor-beta type I receptor kinase domain inhibitors: discovery of an orally bioavailable transforming growth factor-beta receptor type I inhibitor as antitumor agent. J Med Chem, 51(7), 2302-2306. https://doi.org/10.1021/jm701199p
Loomans, H. A., & Andl, C. D. (2014). Intertwining of Activin A and TGFβ Signaling: Dual Roles in Cancer Progression and Cancer Cell Invasion. Cancers (Basel), 7(1), 70-91. https://doi.org/10.3390/cancers7010070
Neuzillet, C., Tijeras-Raballand, A., Cohen, R., Cros, J., Faivre, S., Raymond, E., & de Gramont, A. (2015). Targeting the TGFβ pathway for cancer therapy. Pharmacol Ther, 147, 22-31. https://doi.org/10.1016/j.pharmthera.2014.11.001
Pereira, A. S. et al. (2018). Metodologia da pesquisa cientifica. [free e-book]. Santa Maria: UAB/NTE/UFSM. https://repositorio.ufsm.br/bitstream/handle/1/15824/Lic_Computacao_Metodologia-Pesquisa-Cientifica.pdf?sequence=1.
Sanderson, R. J., & Ironside, J. A. (2002). Squamous cell carcinomas of the head and neck. BMJ, 325(7368), 822-827.
Sun, B. O., Fang, Y., Li, Z., Chen, Z., & Xiang, J. (2015). Role of cellular cytoskeleton in epithelial-mesenchymal transition process during cancer progression. Biomed Rep, 3(5), 603-610. https://doi.org/10.3892/br.2015.494
Yamaguchi, H., & Condeelis, J. (2007). Regulation of the actin cytoskeleton in cancer cell migration and invasion. Biochim Biophys Acta, 1773(5), 642-652. https://doi.org/10.1016/j.bbamcr.2006.07.001
Yang, L. (2010). TGFbeta, a potent regulator of tumor microenvironment and host immune response, implication for therapy. Curr Mol Med, 10(4), 374-380.
Zhang, B., Halder, S. K., Kashikar, N. D., Cho, Y. J., Datta, A., Gorden, D. L., & Datta, P. K. (2010). Antimetastatic role of Smad4 signaling in colorectal cancer. Gastroenterology, 138(3), 969-980.e961-963. https://doi.org/10.1053/j.gastro.2009.11.004
Zhang, S., Sun, W. Y., Wu, J. J., & Wei, W. (2014). TGF-β signaling pathway as a pharmacological target in liver diseases. Pharmacol Res, 85, 15-22. https://doi.org/10.1016/j.phrs.2014.05.005
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Copyright (c) 2021 Arthur Silva Rezende; Anna Cecília Dias Maciel Carneiro; Bruna Raphaela Oliveira Silva; Simone de Sales Costa Moreira Carboni; Virginia Oliveira Crema
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