Laboratório de Hemato-Oncologia Celular e Molecular, Programa de Hemato-Oncologia Molecular, Instituto Nacional de Câncer (INCA), Rio de Janeiro 20231-050, Brazil.
Programa de Pós-Graduação Strictu Sensu em Oncologia, INCA, Rio de Janeiro 20231-050, Brazil.
Cells. 2019 May 24;8(5):500. doi: 10.3390/cells8050500.
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.
P-糖蛋白（Pgp/ABCB1）过表达与多药耐药（MDR）表型相关，因此导致癌症化疗失败。然而，参与细胞死亡失调的分子也可能支持 MDR。肿瘤坏死因子-α（TNF-α）是一种重要的细胞因子，它可能触发细胞死亡或肿瘤生长。在这里，我们通过细胞外囊泡（膜微颗粒（MP））研究了癌细胞在自我维持和促进细胞恶性肿瘤中的作用，这些囊泡可以转运 Pgp 和 TNF-α分子。通过在体外使用经典的 MDR 模型，我们发现内源性 TNF-α和 Pgp 之间存在正相关，这可能有利于重组 TNF-α（rTNF-α）的非细胞毒性作用。我们还发现了涉及 rTNF-α孵育和 TNF-α调节的正反馈。另一方面，rTNF-α诱导 Pgp 表达水平降低，并有助于降低 Pgp 外排功能。我们的结果还表明，亲本和 MDR 细胞自发释放含有内源性 TNF-α和 Pgp 的 MP。然而，这些 MP 无法将其内容物转移到非癌细胞受体中。尽管如此，来自亲本和 MDR 细胞的 MP 提高了非肿瘤细胞的增殖指数。总的来说，我们的结果表明，Pgp 和内源性 TNF-α正向调节癌细胞的恶性肿瘤，并通过 MP 导致正常细胞行为发生变化。
