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Open AccessArticle

TNF-α Modulates P-Glycoprotein Expression and Contributes to Cellular Proliferation via Extracellular Vesicles

1
Laboratório de Hemato-Oncologia Celular e Molecular, Programa de Hemato-Oncologia Molecular, Instituto Nacional de Câncer (INCA), Rio de Janeiro 20231-050, Brazil
2
Programa de Pós-Graduação Strictu Sensu em Oncologia, INCA, Rio de Janeiro 20231-050, Brazil
3
Laboratório de Fisiopatologia, Polo Novo Cavaleiros, Campus UFRJ-Macaé, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-909, Brazil
*
Authors to whom correspondence should be addressed.
Cells 2019, 8(5), 500; https://doi.org/10.3390/cells8050500
Received: 26 March 2019 / Revised: 21 May 2019 / Accepted: 23 May 2019 / Published: 24 May 2019
(This article belongs to the Special Issue ABC Transporters: From Basic Functions to Diseases)
P-glycoprotein (Pgp/ABCB1) overexpression is associated with multidrug resistance (MDR) phenotype and, consequently, failure in cancer chemotherapy. However, molecules involved in cell death deregulation may also support MDR. Tumor necrosis factor-alpha (TNF-α) is an important cytokine that may trigger either death or tumor growth. Here, we examined the role of cancer cells in self-maintenance and promotion of cellular malignancy through the transport of Pgp and TNF-α molecules by extracellular vesicles (membrane microparticles (MP)). By using a classical MDR model in vitro, we identified a positive correlation between endogenous TNF-α and Pgp, which possibly favored a non-cytotoxic effect of recombinant TNF-α (rTNF-α). We also found a positive feedback involving rTNF-α incubation and TNF-α regulation. On the other hand, rTNF-α induced a reduction in Pgp expression levels and contributed to a reduced Pgp efflux function. Our results also showed that parental and MDR cells spontaneously released MP containing endogenous TNF-α and Pgp. However, these MP were unable to transfer their content to non-cancer recipient cells. Nevertheless, MP released from parental and MDR cells elevated the proliferation index of non-tumor cells. Collectively, our results suggest that Pgp and endogenous TNF-α positively regulate cancer cell malignancy and contribute to changes in normal cell behavior through MP. View Full-Text
Keywords: P-glycoprotein; ABCB1; TNF-α; extracellular vesicles; microparticles; drug resistance; MDR P-glycoprotein; ABCB1; TNF-α; extracellular vesicles; microparticles; drug resistance; MDR
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S. Berguetti, T.; S. P. Quintaes, L.; Hancio Pereira, T.; Robaina, M.C.; Cruz, A.L.S.; C. Maia, R.; de Souza, P.S. TNF-α Modulates P-Glycoprotein Expression and Contributes to Cellular Proliferation via Extracellular Vesicles. Cells 2019, 8, 500.

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