Abstract
Stathmin is a p53-target gene, frequently overexpressed in late stages of human cancer progression. Type II High Grade Epithelial Ovarian Carcinomas (HG-EOC) represents the only clear exception to this observation. Here, we show that stathmin expression is necessary for the survival of HG-EOC cells carrying a p53 mutant (p53MUT) gene. At molecular level, stathmin favours the binding and the phosphorylation of p53MUT by DNA-PKCS, eventually modulating p53MUT stability and transcriptional activity. Inhibition of stathmin or DNA-PKCS impaired p53MUT–dependent transcription of several M phase regulators, resulting in M phase failure and EOC cell death, both in vitro and in vivo. In primary human EOC a strong correlation exists between stathmin, DNA-PKCS, p53MUT overexpression and its transcriptional targets, further strengthening the relevance of the new pathway here described. Overall our data support the hypothesis that the expression of stathmin and p53 could be useful for the identification of high risk patients that will benefit from a therapy specifically acting on mitotic cancer cells.
Highlights
The microtubule (MT) destabilizing protein stathmin 1, is a p53 target gene (Murphy et al, 1999; Singer et al, 2007) and has been associated with increasing metastatic potential and drug resistance (Belletti &Baldassarre, 2011)
This result suggested that expression of stathmin and p53 mutant (p53MUT) could be functionally related in High Grade Epithelial Ovarian Carcinomas (HG-epithelial ovarian carcinomas (EOC))
We provide compelling evidences demonstrating that in HG-EOC cells stathmin is necessary for the proper stability and transcriptional activity of p53MUT by favouring the interaction and the phosphorylation of p53MUT by DNA-PK (Fig 8H)
Summary
The microtubule (MT) destabilizing protein stathmin 1 ( known as oncoprotein 18, OP18, or metablastin; Cassimeris, 2002), is a p53 target gene (Murphy et al, 1999; Singer et al, 2007) and has been associated with increasing metastatic potential and drug resistance (Belletti &Baldassarre, 2011). Recent evidence suggests that accumulation of mutant p53 (p53MUT) represents the first event in the development of type II HG-EOC (Karst & Drapkin, 2010) These observations make type II HG-EOC an extremely interesting model to clarify how p53MUT is stabilized in human tumours and which are its downstream effectors during the early stages of carcinogenesis. Both in human and mouse models, mutations in p53 do not account per se for the accumulation of the protein and it is well established that high expression of p53MUT is mostly found in advanced cancers (Goh et al, 2011). Clinical evidences suggest that overexpression of p53MUT is linked to EOCs chemosensitivity, especially when TAX is used (Cassinelli et al, 2001; Lavarino et al, 2000)
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