Abstract
Glioblastoma (grade IV glioma) is the most common and aggressive adult brain tumor. A better understanding of the biology of glioblastoma cells is crucial to identify molecular targets stimulating cell death. NPM1 (nucleophosmin) is a multifunctional chaperone that plays an important role in cancer development. Herein, NPM1 was analyzed by immunohistochemistry in human astrocytic gliomas. NPM1 was detected in all tumors but with a significantly higher staining intensity in grade IV than in low grade tumors. Depletion of NPM1 had only modest effects on the viability of U251MG, U1242MG, and U343MGa Cl2:6 glioma cells, despite alterations in nucleolar morphology. Glioma cell cultures depleted of NPM1 exposed to micromolar levels of actinomycin D were more prone to cell death (apoptosis) compared to cultures retaining NPM1. We had previously found that NPM1 binds to linker histone H1.5. Here we could show that silencing of H1.5 triggered glioma cell apoptosis as evidenced by a marked increase in both the numbers of cleaved caspase-3+ cells and in the amounts of cleaved PARP. Enforced expression of NPM1 suppressed apoptosis in H1.5 depleted glioma cells. Although our studies would suggest little effectiveness of targeting NPM1 alone there could be potential using it as a combination treatment.
Highlights
Breast[11], colon[12], bladder[13], prostate[14], and the thyroid[15]
We found that all glioma cell lines tested by us so far, including U343MGa Cl2:6, U343MG, U118MG, U178MG and U1240MG stained positive for NPM1 (Fig. 2A)
This is in line with a study showing increased expression of NPM1 in grade III and IV tumors, while grade II astrocytomas were found to be similar to non-neoplastic brain tissue[17]
Summary
Breast[11], colon[12], bladder[13], prostate[14], and the thyroid[15]. It has been found to be overexpressed in gliomas at both mRNA and protein levels when compared to normal brain[16,17,18,19]. Several different types of cancer cells with elevated levels of NPM1 are more resistant to UV or hypoxia induced apoptosis than those with low expression[27]. Such anti-apoptotic functions have been connected with NPM1 ́s ability to prevent p53’s localization to mitochondria[28]. Npm[1] is an essential protein for normal development and knockout mice display aberrant organogenesis resulting in death of the mice between embryonic day E11.5 and E16.5 due to anemia[30]. Analysis of neural tissues revealed marked apoptosis suggesting a crucial function of Npm[1] in normal brain development[30]
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