Pentamidine inhibit S100A4 - p53 interaction and decreases cell proliferation activity

• Published in: Archives of biochemistry and biophysics 2020-09, Vol.691, p.108442-108442, Article 108442
• Main Authors: Katte, Revansiddha H., Chou, Ruey-Hwang, Yu, Chin
• Format: Article
• Language: English
• Subjects: High ambiguity driven protein-protein docking (HADDOCK); Nuclear magnetic resonance; p53 N TAD (1–73); S100A4
• ISSN: 0003-9861; 1096-0384
• DOI: 10.1016/j.abb.2020.108442

Metastasis-associated S100A4 protein is a small calcium-binding protein typically overexpressed in several tumor forms, and it is widely accepted that S100A4 plays a significant role in the metastasis of cancer. Tumor suppressor p53 is one of the S100A4's main targets. Previous reports show that through p53, S100A4 regulates collagen expression and cell proliferation. When S100A4 interacts with p53, the S100A4 destabilizes wild type p53. In the current study, based on 1H–15N HSQC NMR experiments and HADDOCK results, S100A4 interacts with the intrinsically unstructured transactivation domain (TAD) of the protein p53 and the pentamidine molecules in the presence of calcium ions. Our results suggest that the p53 TAD and pentamidine molecules share similar binding sites on the S100A4 protein. This observation indicates that a competitive binding mechanism can interfere with the binding of S100A4-p53 and increase the level of p53. Also, we compare different aspects of p53 activity in the WST-1 test using MCF 7 cells. We found that the presence of a pentamidine molecule results in higher p53 activity, which is also reflected in less cell proliferation. Collectively, our results indicate that disrupting the S100A4-p53 interaction would prevent cancer progression, and thus S100A4-p53 inhibitors provide a new avenue for cancer therapy. [Display omitted] •The interaction between S100A4/p53TAD and S100A4/pentamidine were investigated by NMR spectroscopy.•The complex models were generated from NMR restraints using HADDOCK program.•The interface area of the p53TAD and pentamidine molecules that share similar binding sites on the S100A4 protein.•The pentamidine drug molecule inhibit protein-protein interactions.