Cancer-associated S100P protein binds and inactivates p53, permits therapy-induced senescence and supports chemoresistance
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Adriana Gibadulinova1, Michal Pastorek2, Pavel Filipcik1, Peter Radvak1, Lucia Csaderova1, Borivoj Vojtesek2, Silvia Pastorekova1,2
1Institute of Virology, Biomedical Research Center, Slovak Academy of Sciences, Bratislava, Slovak Republic
2Regional Centre for Applied Molecular Oncology, Masaryk Memorial Cancer Institute, Brno, Czech Republic
Silvia Pastorekova, e-mail: [email protected]
Keywords: S100P calcium-binding protein, p53 tumor suppressor, HDM2, cell death, therapy-induced senescence
Received: September 09, 2015 Accepted: February 20, 2016 Published: March 9, 2016
S100P belongs to the S100 family of calcium-binding proteins regulating diverse cellular processes. Certain S100 family members (S100A4 and S100B) are associated with cancer and used as biomarkers of metastatic phenotype. Also S100P is abnormally expressed in tumors and implicated in migration-invasion, survival, and response to therapy. Here we show that S100P binds the tumor suppressor protein p53 as well as its negative regulator HDM2, and that this interaction perturbs the p53-HDM2 binding and increases the p53 level. Paradoxically, the S100P-induced p53 is unable to activate its transcriptional targets hdm2, p21WAF, and bax following the DNA damage. This appears to be related to reduced phosphorylation of serine residues in both N-terminal and C-terminal regions of the p53 molecule. Furthermore, the S100P expression results in lower levels of pro-apoptotic proteins, in reduced cell death response to cytotoxic treatments, followed by stimulation of therapy-induced senescence and increased clonogenic survival. Conversely, the S100P silencing suppresses the ability of cancer cells to survive the DNA damage and form colonies. Thus, we propose that the oncogenic role of S100P involves binding and inactivation of p53, which leads to aberrant DNA damage responses linked with senescence and escape to proliferation. Thereby, the S100P protein may contribute to the outgrowth of aggressive tumor cells resistant to cytotoxic therapy and promote cancer progression.
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