Cancer-associated S100P protein binds and inactivates p53, permits therapy-induced senescence and supports chemoresistance.

Adriana Gibadulinova,Silvia Pastorekova,Peter Radvak,Michal Pastorek,Borivoj Vojtesek,Pavel Filipcik,Lucia Csaderova

doi:10.18632/oncotarget.7999

Adriana Gibadulinova, Silvia Pastorekova + Show 5 more

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https://doi.org/10.18632/oncotarget.7999

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Abstract

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.

Highlights

S100P belongs to the S100 family of calciumbinding proteins linked with various diseases
These discordant effects may be caused by S100P crosstalk with diverse pathways in different tumor types, including activation of the MAPK/ERK, PI3K/AKT and NFkB signaling mediated by the binding of the extracellular S100P to RAGE receptor [10] and, based on the analogy with other S100 proteins, activation of apoptosis-related pathways driven by the JNK stress kinase and/or p53 tumor suppressor protein [1]
We found that S100P could bind both wild-type and mutant p53 in a calcium-dependent manner (Figure 1A, 1B)

Summary

Introduction

S100P belongs to the S100 family of calciumbinding proteins linked with various diseases. Overexpression of S100P was shown to increase the chemosensitivity of ovarian cells [9]. These discordant effects may be caused by S100P crosstalk with diverse pathways in different tumor types, including activation of the MAPK/ERK, PI3K/AKT and NFkB signaling mediated by the binding of the extracellular S100P to RAGE receptor [10] and, based on the analogy with other S100 proteins, activation of apoptosis-related pathways driven by the JNK stress kinase and/or p53 tumor suppressor protein [1]. Stability and activity of the wild-type p53 protein is determined by a number of posttranslational modifications, primarily by the phosphorylation, methylation and acetylation These modifications determine the interactions of www.impactjournals.com/oncotarget p53 with its binding partners, which in turn affect the p53 modifications, stability and activity [13]

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