Regulation of Chemosensitivity in Human Medulloblastoma Cells by p53 and the PI3 Kinase Signaling Pathway.

Autor:	Naeem A; Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC.; Health Research Governance Department, Ministry of Public Health, Doha, Qatar., Harish V; Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC., Coste S; Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC., Parasido EM; Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC., Choudhry MU; Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC., Kromer LF; Department of Neuroscience, Georgetown University Medical Center, Washington, DC., Ihemelandu C; Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC., Petricoin EF; George Mason University, Center for Applied Proteomics and Molecular Medicine, Manassas, Virginia., Pierobon M; George Mason University, Center for Applied Proteomics and Molecular Medicine, Manassas, Virginia., Noon MS; Data Science Institute, University of Arizona, Texas, Arizona., Yenugonda VM; Department of Drug Discovery and Nanomedicine, Saint John's Cancer Institute, Santa Monica, California., Avantaggiati M; Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC., Kupfer GM; Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC.; Department of Pediatrics, Georgetown University Medical Center, Washington, DC., Fricke S; Department of Radiology, Georgetown University Medical Center, Washington, DC.; Center for Translational Imaging, Georgetown University Medical Center, Washington, DC., Rodriguez O; Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC.; Center for Translational Imaging, Georgetown University Medical Center, Washington, DC., Albanese C; Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC. albanese@georgetown.edu.; Department of Radiology, Georgetown University Medical Center, Washington, DC.; Center for Translational Imaging, Georgetown University Medical Center, Washington, DC.
Jazyk:	angličtina
Zdroj:	Molecular cancer research : MCR [Mol Cancer Res] 2022 Jan; Vol. 20 (1), pp. 114-126. Date of Electronic Publication: 2021 Oct 11.
DOI:	10.1158/1541-7786.MCR-21-0277
Abstrakt:	In medulloblastoma, p53 expression has been associated with chemoresistance and radiation resistance and with poor long-term outcomes in the p53 -mutated sonic hedgehog, MYC-p53, and p53-positive medulloblastoma subgroups. We previously established a direct role for p53 in supporting drug resistance in medulloblastoma cells with high basal protein expression levels (D556 and DAOY). We now show that p53 genetic suppression in medulloblastoma 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 p110α/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 β4 (Tβ4), induced p-AKT S473 in both p53-high and p53-low cells, enhancing chemosensitivity in D556 cells while enhancing chemoresistance in D283 and UW228 cells. IMPLICATIONS: Collectively, we identified an unexpected role for the PI3K signaling in enhancing cell death in medulloblastoma cells with high basal p53 expression. These studies indicate that levels of p53 immunopositivity may serve as a diagnostic marker of chemotherapy resistance and for defining therapeutic targeting. (©2021 The Authors; Published by the American Association for Cancer Research.)
Databáze:	MEDLINE
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