Research Papers:

Could a plant derived protein potentiate the anticancer effects of a stem cell in brain cancer?

Camila Ramalho Bonturi, Helena Motaln, Mariana Cristina Cabral Silva, Bruno Ramos Salu, Marlon Vilela de Brito, Luciana de Andrade Luz Costa, Heron Fernandes Vieira Torquato, Natalia Neto dos Santos Nunes, Edgar Julian Paredes-Gamero, Tamara Lah Turnšek and Maria Luiza Vilela Oliva _

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Oncotarget. 2018; 9:21296-21312. https://doi.org/10.18632/oncotarget.25090

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Camila Ramalho Bonturi1, Helena Motaln2, Mariana Cristina Cabral Silva1, Bruno Ramos Salu1, Marlon Vilela de Brito1, Luciana de Andrade Luz Costa1, Heron Fernandes Vieira Torquato3, Natalia Neto dos Santos Nunes1, Edgar Julian Paredes-Gamero3, Tamara Lah Turnšek2 and Maria Luiza Vilela Oliva1

1Biochemistry Department, Federal University of São Paulo, 04044-020, São Paulo - SP, Brazil

2Genetic Toxicology and Cancer Biology Department, National Institute of Biology, 1000, Ljubljana, Slovenia

3Biophysics Department, Federal University of São Paulo, 04039-032, São Paulo-SP, Brazil

Correspondence to:

Maria Luiza Vilela Oliva, email: [email protected]

Tamara Lah Turnšek, email: [email protected]

Keywords: brain cancer; glioma; stem cells; inhibitors; invasion

Received: August 31, 2017     Accepted: February 26, 2018     Published: April 20, 2018


Glioblastoma is the most aggressive brain tumor with poor overall survival bellow 2 years. The natural compounds with anti-cancer properties, are thus gaining attention for possible adjuvant GBM treatment. In various cancer models Enterolobium contortisiliquum Trypsin Inhibitor (EcTI) proved to have anti-cancer effects. Here, we investigated the EcTI effects on GBM U87 cells and on mesenchymal stem cells (MSC) compared to their direct coculture (MSC/U87). MSC are present in tumor stroma, modulating GBM cells phenotype, and also represent potential drug delivery vehicle due to their tumor tropism. We showed that in p53-wild type U87 cells, metabolic activity was less affected by EcTI as in MSC monocuture, but the metabolic rate of mixed coculture was significantly reduced at lower EcTI concentration. Under coculture condition, EcTI potentiated MSC induced cell cycle arrest, possible due to highly increased p53, p21 and lower D1 expression, but there was no effect on apoptosis. Accordingly, in the coculture EcTI also enhanced Ca2+ signalling mediated via bradykinin receptor 2, being associated with nitric oxide release that highly impaired proliferation and invasion. The mechanism did not seem to involve changes in cell adhesion but rather it down-regulated the β1 integrin signaling with associated p-FAK in U87 cells, both supporting inhibition of invasion. Finally, some cytokines were down-regulated, indicating that EcTI inhibition of signalling might be mediated by cytokines. In conclusion, these results indicate that in cocultured MSC/U87 cells EcTI impairs the metabolic activity, proliferation, and reduced invasion, possibly associated with observed cytokines secretion. In this context, we confirmed that the plant derived protein potentiated the anticancer effects, induced by MSC, as represented by GBM U87 cell line.

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