PRJNA766838
Enhancing therapeutic responses in Medulloblastoma via PI3K
In medulloblastoma (MB), p53 expression has been associated with chemo- and radiation-resistance and with poor long-term outcomes in the p53-mutated sonic hedgehog, MYC-p53, and p53-positive MB subgroups. We previously established a direct role for p53 in supporting drug resistance in MB cells with high basal protein expression levels (D556 and DAOY). We now show that p53 genetic suppression in MB cells with low basal p53 protein expression levels (D283 and UW228) significantly reduced drug responsiveness, suggesting opposing roles for low p53 protein expression levels. Mechanistically, the enhanced cell death by p53-knockdown in high-p53 cells was associated with an induction of mTOR/PI3K signaling. Both mTOR inhibition and p110 alpha PIK3CA induction confirmed these findings, which abrogated or accentuated the enhanced chemosensitivity response in D556 cells respectively while converse was seen in D283 cells. Co-treatment with G-actin-sequestering peptide, thymosin beta 4, induced p-AKTS473 in both p53-high and p53-low cells, enhancing chemosensitivity in D556 cells while enhancing chemoresistance in D283 and UW228 cells. Collectively, we identified an unexpected role for the PI3K signaling in enhancing cell death in MB cells with high p53 expression. These studies indicate that levels of p53 immunopositivity may serve as a diagnostic marker of chemotherapy resistance and for defining therapeutic targeting.