4.6 Article

Targeting the TP53/MDM2 axis enhances radiation sensitivity in atypical teratoid rhabdoid tumors

Journal

INTERNATIONAL JOURNAL OF ONCOLOGY
Volume 60, Issue 3, Pages -

Publisher

SPANDIDOS PUBL LTD
DOI: 10.3892/ijo.2022.5322

Keywords

ATRT; SMARCB1; MDM2; TP53; idasanutlin; radiation sensitivity

Categories

Funding

  1. Morgan Adams Foundation Pediatric Research Program
  2. DOD [CA170677]
  3. Cancer Center Support Grant [P30CA046934]
  4. NIH Shared Instrumentation Grant Program [S10 OD023485, S10 OD027023]
  5. University of Colorado Cancer Center grant [P30 CA046934]

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Atypical teratoid rhabdoid tumor (ATRT) is an aggressive pediatric brain tumor. Inhibition of MDM2 can effectively suppress the growth of ATRT cells and induce apoptosis, and it can also enhance the sensitivity of ATRT cells to radiation.
Atypical teratoid rhabdoid tumor (ATRT) is a highly aggressive pediatric brain tumor. Despite radiation, aggressive chemotherapy and autologous stem cell rescue, children usually have a poor survival time. In the present study, the role of TP53/MDM2 interaction in ATRT was investigated. A functional genomic screen identified the TP53/MDM2 axis as a therapeutic target in the central nervous system (CNS) ATRT. Gene expression analysis revealed that all ATRT sub-groups expressed high levels of MDM2, which is a negative regulator of TP53. Using cell viability, colony formation and methylcellulose assays it was found that genetic MDM2 inhibition with short hairpin RNA or chemical MDM2 inhibition with small molecule inhibitors, Nutlin3 and idasanutlin (RG7388) decreased the growth of ATRT cell lines. Furthermore, idasanutlin significantly decreased the growth of intracranial orthotopic ATRT brain tumors, as evaluated using T2 MRI, and prolonged survival time relative to control animals. MRI of intracranial tumors showed that diffusion coefficient, an effective marker for successful treatment, significantly increased with idasanutlin treatment showing tumor necrosis/apoptosis. Immunohistochemistry revealed an increased number of caspase-3-positive cells in the idasanutlin treatment group, confirming the induction of apoptosis in vivo. Using flow cytometry and western blot analysis we show that inhibition of MDM2 enhanced radiation sensitivity in vitro by potentiating DNA damage via the induction of the TP53/Bax/Puma proapoptotic axis. Furthermore, DNA damage was associated with increased mitochondrial reactive oxygen species accumulation. The present study demonstrated that MDM2 expression level was increased in ATRT patient samples and MDM2 inhibition suppressed ATRT cell growth in vitro, and leads to apoptosis in vivo. MDM2 inhibition potentiates DNA damage and sensitizes ATRT cells to radiation. These findings highlight the TP53/MDM2 axis as a rational therapeutic target in CNS ATRT.

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