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

Naeem, Aisha; Harish, Varsha; Coste, Sophie; Parasido, Erika M.; Choudhry, Muhammad Umer; Kromer, Lawrence F.; Ihemelandu, Chukuemeka; Petricoin, Emanuel F.; Pierobon, Mariaelena; Noon, Muhammad Saad; Yenugonda, Venkata Mahidhar; Avantaggiati, Maria; Kupfer, Gary M.; Fricke, Stanley; Rodriguez, Olga; Albanese, Chris

doi:10.1158/1541-7786.mcr-21-0277

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

Journal Article · 31 December 2021 · Molecular Cancer Research

DOI: https://doi.org/10.1158/1541-7786.mcr-21-0277 · OSTI ID:2469734

^[1]; Harish, Varsha ^[2];

^[2]; Parasido, Erika M. ^[2]; Choudhry, Muhammad Umer ^[2]; Kromer, Lawrence F. ^[2]; Ihemelandu, Chukuemeka ^[2]; Petricoin, Emanuel F. ^[3]; Pierobon, Mariaelena ^[3];

^[4]; Yenugonda, Venkata Mahidhar ^[5]; Avantaggiati, Maria ^[2]; Kupfer, Gary M. ^[2]; Fricke, Stanley ^[2];

^[2]; Albanese, Chris ^[2]

Georgetown Univ., Washington, DC (United States). Medical Center; Ministry of Public Health, Doha (Qatar)
Georgetown Univ., Washington, DC (United States). Medical Center
George Mason Univ., Manassas, VA (United States)
Univ. of Arizona, Tucson, AZ (United States)
Saint John's Cancer Institute, Santa Monica, CA (United States)

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.

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Research Organization:: Lawrence Livermore National Laboratory (LLNL), Livermore, CA (United States)

Sponsoring Organization:: USDOE; National Institutes of Health (NIH)

Grant/Contract Number:: AC52-07NA27344

OSTI ID:: 2469734

Journal Information:: Molecular Cancer Research, Journal Name: Molecular Cancer Research Journal Issue: 1 Vol. 20; ISSN 1541-7786

Publisher:: American Association for Cancer Research (AACR)Copyright Statement

Country of Publication:: United States

Language:: English

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