Translocation of intracellular CD24 constitutes a triggering event for drug resistance in breast cancer

Abstract

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.

The Unholy Trinity- Cancer cell plasticity, drug resistance and therapeutic opportunities

“…A recent study has linked CD24, a CSC maker to phenotypic switching and thus induction of cellular plasticity to the MAPK pathway. The cellular localization of CD24 is mediated by p38 MAPK pathway activation with phosphorylation leading to Bcl over-expression resulting in the localization of a high-density of CD24 molecules in the cell membrane 55 A commonly upregulated factor CDLYL2 in breast cancer is observed to mediate the cell plasticity phenomenon by regulating miRNA-124 which in turn impacts both STAT3 and NF-κβ pathways 58 . The overexpression of the CDYL2 lead to changes at morphological and molecular level in the breast cancer cells.…”

Unraveling the dangerous duet between cancer cell plasticity and drug resistance

“…A study by Hugh et al focused on the localization pattern of CD24 indicating the development of plasticity [72]. The cellular localization of CD24 is mediated by p38 MAPK pathway activation with phosphorylation leading to Bcl-2 overexpression in the cell membrane [73] and treatment resistance. Non-genomic factors like estrogen mediate cellular plasticity in the tumor cells that have a propensity toward undergoing EMT.…”

CD24: A Novel Target for Cancer Immunotherapy

“…Thus, the inhibition of autophagy through the PI3K/Akt pathway seems to be involved in the development of CD24-mediated chemoresistance [ 53 ]. Another mechanism of resistance may involve the activation of MAPK-related pathways, resulting in temporary inhibition of cell proliferation [ 54 ]. CD24 may also enhance cytotoxicity from DNA-damaging agents through the disruption of NF-κB signaling [ 55 ].…”