Identificação de um tandem CD24/p38MAPK envolvido na plasticidade celular e na resistência à quimioterapia na linhagem agressiva de câncer de mama MDA-MB-231

Abstract

Intratumor Heterogeneity (ITH) is one of the main responsible for chemoresistance. The Cluster Differentitation 24 (CD24) is a GPI-anchored glycoprotein closely related with ITH and it is identified as a Cancer Stem Cell (CSC) marker. In invasive breast cancer, CD24 is overexpressed in 84,6% of patients. Hence, the aim of our study was to investigate the role of CD24 in the sensibility of the aggressive MDA-MB-231 cell line to doxorubicin, establishing a correlation between CD24 expression and differential activation of signaling pathway networks. A relatioship was established between the differential use of MAPKs and the presence of CD24 on cell membrane. More specifically, a preferential activation of p38 MAPK was constantly observed in CD24+ cells which correlated with a higher proliferative activity of these cells. During in vitro chemotherapy, we have shown a rapid translocation of CD24 towards membrane, few hours after treatment, thanks to an intracellular reservoir of CD24 immediately available. This phenotype switching was associated with a constitutive activation of p38MAPK leading to cell reprogramming exemplified by the trimethylation of H3K9 and the overexpression of the anti-apoptotic protein Bcl-2. Importantly, the use of p38 inhibitor sensitized cells to doxorubicin that was in accord with its ability to reduce Bcl-2 levels and consequently to overcome drug resistance. Besides, we accompanied the journey of cells after treatment with doxorubicin starting from their switching to CD24+ state and continuing through their entry into senescence-like state and reawakening after several weeks of culture. We presented an insight into the molecular underpinnings of the “reawakened” phenotypes that correlated with their higher chemoresistance. This may be put in parallel with cancer relapse. In conclusion, our data indicate that strategy to prevent drug resistance controlling signaling network associated with CSC marker is workable in aggressive breast cancer.