2. Academic Validation
  3. TNF-α Modulates P-Glycoprotein Expression and Contributes to Cellular Proliferation via Extracellular Vesicles

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

  • Cells. 2019 May 24;8(5):500. doi: 10.3390/cells8050500.
Tandressa Berguetti 1 2,  Lucas S P Quintaes 3,  Thais Hancio 4 5,  Marcela C Robaina 6,  André L S Cruz 7,  Raquel C Maia 8,  Paloma Silva de Souza 9
Affiliations

Affiliations

  • 1 Laboratório de Hemato-Oncologia Celular e Molecular, Programa de Hemato-Oncologia Molecular, Instituto Nacional de Câncer (INCA), Rio de Janeiro 20231-050, Brazil. tata.berguetti@hotmail.com.
  • 2 Programa de Pós-Graduação Strictu Sensu em Oncologia, INCA, Rio de Janeiro 20231-050, Brazil. tata.berguetti@hotmail.com.
  • 3 Laboratório de Hemato-Oncologia Celular e Molecular, Programa de Hemato-Oncologia Molecular, Instituto Nacional de Câncer (INCA), Rio de Janeiro 20231-050, Brazil. lucas.s.p.quintaes@gmail.com.
  • 4 Laboratório de Hemato-Oncologia Celular e Molecular, Programa de Hemato-Oncologia Molecular, Instituto Nacional de Câncer (INCA), Rio de Janeiro 20231-050, Brazil. thais.hancio@gmail.com.
  • 5 Programa de Pós-Graduação Strictu Sensu em Oncologia, INCA, Rio de Janeiro 20231-050, Brazil. thais.hancio@gmail.com.
  • 6 Laboratório de Hemato-Oncologia Celular e Molecular, Programa de Hemato-Oncologia Molecular, Instituto Nacional de Câncer (INCA), Rio de Janeiro 20231-050, Brazil. mrobaina@ymail.com.
  • 7 Laboratório de Fisiopatologia, Polo Novo Cavaleiros, Campus UFRJ-Macaé, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-909, Brazil. andrecruz@macae.ufrj.br.
  • 8 Laboratório de Hemato-Oncologia Celular e Molecular, Programa de Hemato-Oncologia Molecular, Instituto Nacional de Câncer (INCA), Rio de Janeiro 20231-050, Brazil. rcmaia@inca.gov.br.
  • 9 Laboratório de Hemato-Oncologia Celular e Molecular, Programa de Hemato-Oncologia Molecular, Instituto Nacional de Câncer (INCA), Rio de Janeiro 20231-050, Brazil. paloma.inca@gmail.com.
PMID: 31137684 DOI: 10.3390/cells8050500
Abstract

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.

Keywords

ABCB1; MDR; P-glycoprotein; TNF-α; drug resistance; extracellular vesicles; microparticles.

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