Abstract
S100P, a small calcium-binding protein, associates with the p53 protein with micromolar affinity. It has been hypothesized that the oncogenic function of S100P may involve binding-induced inactivation of p53. We used 1H-15N HSQC experiments and molecular modeling to study the molecular interactions between S100P and p53 in the presence and absence of pentamidine. Our experimental analysis indicates that the S100P-53 complex formation is successfully disrupted by pentamidine, since S100P shares the same binding site for p53 and pentamidine. In addition, we showed that pentamidine treatment of ZR-75-1 breast cancer cells resulted in reduced proliferation and increased p53 and p21 protein levels, indicating that pentamidine is an effective antagonist that interferes with the S100P-p53 interaction, leading to re-activation of the p53-21 pathway and inhibition of cancer cell proliferation. Collectively, our findings suggest that blocking the association between S100P and p53 by pentamidine will prevent cancer progression and, therefore, provide a new avenue for cancer therapy by targeting the S100P-p53 interaction.
Highlights
Wiesława LeśniakThe transcription activator protein p53 plays a crucial role in regulating tumor formation, suppression, and cancer prevention
The results further provide the evidence of pentamidine efficacy in vitro by reducing cell proliferation and increasing the p53 protein level, suggesting the role of pentamidine as an effective antagonist to interfere the S100P-p53 interaction and reactivate normal p53 function
Cancer Cells the absence and presence of pentamidine, we found that pentamidine-bound S100P resiThe WST-1 cell proliferation assay provides an important strategy to check the efficacy
Summary
Wiesława LeśniakThe transcription activator protein p53 plays a crucial role in regulating tumor formation, suppression, and cancer prevention. Protein, a negative regulator of the p53 protein [4,5,6]. It is controlled by a variety of post-translational modifications and interactions with a wide range of target signaling proteins [4]. The N-terminal region, representing the transactivation domain (TAD) and comprising the first 73 residues (p531-73 ), is intrinsically disordered [7], which facilitates conformational adaptability upon binding to multiple target proteins and confers high specificity as seen in proteins involved in signaling networks [8,9]
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