NYMC Faculty Publications

The Impact of Arsenic Trioxide and All-Trans Retinoic Acid on p53 R273H-Codon Mutant Glioblastoma

Author Type(s)

Faculty

DOI

10.1176/appi.neuropsych.13080173

Journal Title

Tumour Biology

First Page

4567

Last Page

4580

Document Type

Article

Publication Date

5-1-2014

Department

Medicine

Keywords

Amino Acid Sequence, Antineoplastic Agents, Apoptosis, Arsenic Trioxide, Arsenicals, Brain Neoplasms, Cell Differentiation, Cell Line, Tumor, Cell Proliferation, Codon, Extracellular Signal-Regulated MAP Kinases, Genes, p53, Glioblastoma, Humans, Molecular Sequence Data, Mutation, Neoplastic Stem Cells, Oxides, Tretinoin

Disciplines

Medicine and Health Sciences

Abstract

Glioblastoma (GBM) is the most common primary brain tumor in adults and demonstrates a 1-year median survival time. Codon-specific hotspot mutations of p53 result in constitutively active mutant p53, which promotes aberrant proliferation, anti-apoptosis, and cell cycle checkpoint failure in GBM. Recently identified CD133(+) cancer stem cell populations (CSC) within GBM also confer therapeutic resistance. We studied targeted therapy in a codon-specific p53 mutant (R273H) created by site-directed mutagenesis in U87MG. The effects of arsenic trioxide (ATO, 1 μM) and all-trans retinoic acid (ATRA, 10 μM), possible targeted treatments of CSCs, were investigated in U87MG neurospheres. The results showed that U87-p53(R273H) cells generated more rapid neurosphere growth than U87-p53(wt) but inhibition of neurosphere proliferation was seen with both ATO and ATRA. U87-p53(R273H) neurospheres showed resistance to differentiation into glial cells and neuronal cells with ATO and ATRA exposure. ATO was able to generate apoptosis at high doses and proliferation of U87-p53(wt) and U87-p53(R273H) cells was reduced with ATO and ATRA in a dose-dependent manner. Elevated pERK1/2 and p53 expression was seen in U87-p53(R273H) neurospheres, which could be reduced with ATO and ATRA treatment. Additionally, differential responses in pERK1/2 were seen with ATO treatment in neurospheres and non-neurosphere cells. In conclusion, codon-specific mutant p53 conferred a more aggressive phenotype to our CSC model. However, ATO and ATRA could potently suppress CSC properties in vitro and may support further clinical investigation of these agents.

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