Tumor cells capture the signaling pathways used by normal tissue to promote their own survival and dissemination and among them, the NF-κB and MAPK pathways (ERK, JNK and p38). MAPK activation has ambiguous effects on tumor cell fate depending on cell type, cancer stage and the engaged MAPK isoforms. A synthetic peptide named LyeTx II, derived from the venom of the Brazilian spider Lycosa erythrognatha, was capable of increasing MDA-MB-231 aggressive breast cancer cell proliferation as indicated by MTT and BrdU (5-bromo-2'-deoxyuridine) incorporation assay and cell migration. A correlation has been established between the accelerated proliferation and migration observed in the presence of LyeTx II and the upregulation of p38 MAPK phosphorylation. The use of the selective inhibitor of p38α/β (SB203580) abrogated the peptide effect in MDA-MB-231 cells. Besides, an augment of the canonical NF-κB pathway activation considered as crucial in cancer progression was noted after cell incubation with LyeTx II. Importantly, activation of p38 and NF-κB pathways was dependent on TAK1 activity. Together, these data suggest that TAK1-p38 pathway may represent an interesting target for treatment of aggressive breast cancers.

The capacity of tumor cells to shift dynamically between different states could be responsible for chemoresistance and has been commonly linked to the acquisition of stem cell properties. Here, we have evaluated the phenotype switching associated with drug resistance in breast cancer cell lines and cell lineage obtained from Brazilian patients. We have highlighted the role of the cancer stem cell marker CD24 in the dynamics of cell plasticity and the acquirement of drug resistance. We showed that the translocation of CD24 from cytosol to cell membrane is a triggering event for the phenotype change of breast tumor cells exposed to drug stress. Here, we provide evidence that the phenotype switching is due to the presence of a cytosolic pool of CD24. Importantly, the cellular localization of CD24 was correlated with the changes in the dynamics of p38 MAPK activation. A strong and continuous phosphorylation of the p38 MAPK led to the overexpression of Bcl-2 after treatment in persistent cells presenting high density of CD24 on cell membrane. This phenotype enabled the cells to enter in slow-down of cell cycle, after which several weeks later, the dormant cells proliferated again. Importantly, the use of a p38 activity inhibitor sensitized cells to drug treatment and avoided chemoresistance.

This study continues to explore the plasticity of Toll-like receptor 2 (TLR2) previously described in immune response during Trypanosoma cruzi infection. Here, we have shown that Ly6ChiTLR2hi monocytes were involved in TNF-α and IL-12 production, whereas Ly6CloTLR2hi monocytes were mainly committed to IL-10 and TNF-α production during T. cruzi infection independently of TLR agonist used (i.e. TLR2 or TLR9 agonists). Another difference between the monocyte populations is that the adapter Mal (encoded by TIRAP) has appeared crucial for the cytokine production by Ly6Clo but not by Ly6Chi monocytes. The protein Mal was necessary to induce cytokine synthesis by Ly6Clo monocytes after triggering TLR2 or TLR9. Finally, our data have suggested that TLR2, TLR9, and Mal/TIRAP controlled differentially the emergence of the different TLR2hi monocyte populations in the spleen. In summary, this study highlights the central role of the TLR2/Mal tandem in the distinct activity among the monocyte subsets during T. cruzi infection. Such findings provide a basis for understanding the challenge posed by the use of TLR2 agonist in immunotherapy.

Chagas disease (CD) is caused by the parasitic protozoan T. cruzi. The progression of CD in ~30% of patients results in Chagasic Cardiomyopathy (CCM). Currently, it is known that the inflammatory system plays a significant role in the CCM. Interferon-gamma (IFN-γ) is the major cytokine involved in parasitemia control but has also been linked to CCM. The L-type calcium current (I_Ca,L) is crucial in the excitation/contraction coupling in cardiomyocytes. Thus, we compared I_Ca,L and the mechanical properties of cardiomyocytes isolated from infected wild type (WT) and IFN-γ^(−/−) mice in the first stage of T. cruzi infection. Using the patch clamp technique, we demonstrated that the infection attenuated I_Ca,L in isolated cardiomyocytes from the right and left ventricles of WT mice at 15 days post-infection (dpi), which was not observed in the IFN-γ^(−/−) cardiomyocytes. However, I_Ca,L was attenuated between 26 and 30 dpi in both experimental groups. Interestingly, the same profile was observed in the context of the mechanical properties of isolated cardiomyocytes from both experimental groups. Simultaneously, we tracked the mortality and MCP-1, TNF-α, IL-12, IL-6, and IL-10 serum levels in the infected groups. Importantly, the IFN-γ^(−/−) and WT mice presented similar parasitemia and serum inflammatory markers at 10 dpi, indicating that the modifications in the cardiomyocyte functions observed at 15 dpi were directly associated with IFN-γ^(−/−) deficiency. Thus, we showed that IFN-γ plays a crucial role in the electromechanical remodeling of cardiomyocytes during experimental T. cruzi infection in mice.