Translocation of Intracellular CD24 Towards Cell Membrane Constitutes a Triggering Event for Drug Resistance in Breast Tumor Cell: Correlation With Dynamics of p38MAPK Activation

Abstract BackgroundThe adaptation 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 provided new elements concerning the role of the Cancer Stem Cell marker CD24 in the dynamics of tumor cell plasticity and the acquirement of drug resistance in breast cancer.MethodologyBreast cancer cell lines and cell lineage obtained from Brazilian patients were treated with cytotoxic and non-cytotoxic drugs and the phenotype switching associated with drug resistance was evaluated. Different markers were quantified like the expression of CD24 through microscopy and FACS, the regulation of pro- and anti-apoptotic proteins Bax and Bcl-2, epigenetic changes and MAPK activation using western blotting in wild type and CD24 silencing cells. ResultsThe translocation of CD24 from cytosol to cell membrane was a triggering event for the phenotype change of tumor cells exposed to drug stress. Importantly, this phenomenon was observed in all the cells of the different population that was rendered possible thanks to the presence of an intracellular pool of CD24 in each given breast tumor cell. In these CD24+ cells, a strong and continuous phosphorylation of the p38 MAPK leading to drug resistance through the tri-methylation of H3K9 and overexpression of the anti-apoptotic protein Bcl-2 was observed. Importantly, the drug-resistant CD24+ cells entered into slow-down of cell cycle and restarted to proliferate after several weeks. The reawakened cells presented constitutive p38 activation, higher drug resistance and higher migration capacity. Notably, the use of a p38 activity inhibitor sensitized cells to drug treatment and avoided the appearance of chemoresistance.Conclusions/significance In this study, we have associated the cellular localization of CD24 with the changes in the dynamics of p38MAPK activation in breast tumor cells under drug stress. The tandem CD24/p38 plays a crucial role in the acquisition of drug resistance and new cell identity. The use of p38 inhibitor was able to disrupt this partnership and consequently to avoid chemotherapy-induced cell state transition. These results suggest that targeting p38 in breast cancer can overcome adaptive resistance to doxorubicin treatment.