Deficiency of the tumour suppressor
merlin leads to the development of
schwannomas,
meningiomas and
ependymomas occurring spontaneously or as a part of the
hereditary disease Neurofibromatosis type 2 (NF2).
Merlin loss is also found in a proportion of other
cancers like
mesothelioma,
melanoma,
breast cancer and
glioblastoma. The tumour suppressor/
transcription factor p53 regulates proliferation, survival and differentiation and its deficiency plays a role in the development of many tumours. 53 can be negatively regulated by FAK, PI3K/AKT and MDM2 and possibly positively regulated by
merlin in different cell lines. In this study we investigated the role of p53 in
merlin-deficient tumours. Using our in vitro model of primary human
schwannoma cells we have previously demonstrated that FAK is overexpressed/activated and localises into the nucleus of
schwannoma cells increasing proliferation. AKT is strongly activated via
platelet-derived growth factor (PDGF) - and
insulin-like growth factor 1 (IGF1) - receptors increasing survival. Here we investigated p53 regulation and its role in proliferation and survival of human primary
schwannoma cells using western blotting, immunocytochemistry, immunohistochemistry and proliferation, survival and
transcription factor assays. In human primary
schwannoma cells p53 was found to be downregulated while MDM2 was upregulated leading to increased cell proliferation and survival. p53 is regulated by
merlin involving FAK, AKT and MDM2.
Merlin reintroduction into
schwannoma cells increased p53 levels and activity, and treatment with
Nutlin-3, a drug which increases p53 stability by disrupting the p53/MDM2 complex, decreased tumour growth and reduced cell survival. These findings are important to dissect the mechanisms responsible for the development of
merlin-deficient tumours and to identify new therapeutic targets. We suggest that
Nutlin-3, possibly in combination with FAK or PI3K inhibitors, can be employed as a novel treatment for
schwannoma and other
merlin-deficient tumours.