Microparticles induce multifactorial resistance through oncogenic pathways independently of cancer cell type.
Bottom Line: By co-culturing MP derived from MDR-positive cells with recipient cells, we showed that sensitive cells accumulated Pgp, IAP proteins and mRNA.In addition, MP promoted microRNA transfer and NFκB and Yb-1 activation.Therefore, our results indicate that MP can induce a multifactorial phenotype in sensitive cancer cells.
Affiliation: Program of Hemato-Oncology Molecular, Brazilian National Cancer Institute, Rio de Janeiro, Brazil.Show MeSH
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Mentions: Constitutive activation of the NFκB pathway has been observed in several solid and hematological neoplasms and has been associated with oncogenesis by controlling several key mechanisms, including anti-apoptotic and resistance gene regulation.23 Our results demonstrated that BIRC4 mRNA was not contained in MP derived from resistant cells (Fig.2b). However, we observed BIRC4 mRNA upregulation in both recipient cells after co-culturing with MDR-positive donor cells and MDR-positive cell-derived MP (Fig.3c and Suppl. Fig. S2, respectively). Thus, we evaluated NFκB pathway activation through IκBα regulation and NFκB subcellular localization. IκBα levels were reduced in A549 and MCF7 cells after co-culturing with MDR cell-derived MP (Fig.5a). Moreover, we observed a subcellular redistribution of NFκB with predominant nuclear localization after co-culturing (Fig.5b,c). These results strongly suggest the functional NFκB pathway involvement in intrinsic BIRC4 gene regulation. Likewise, nuclear NFκB may have contributed to intrinsic ABCB1 and IAP expression in recipient cells (Fig.3).
Affiliation: Program of Hemato-Oncology Molecular, Brazilian National Cancer Institute, Rio de Janeiro, Brazil.