Ahmed, Ahmed A, Greenhalf, William 
ORCID: 0000-0002-1865-3195, Palmer, Daniel H, Williams, Nicole, Worthington, Jenny, Arshad, Tariq, Haider, Shozeb, Alexandrou, Effrosyni, Guneri, Dilek, Waller, Zoe AE et al (show 1 more authors)
(2023)
The Potent G-Quadruplex-Binding Compound QN-302 Downregulates S100P Gene Expression in Cells and in an In Vivo Model of Pancreatic Cancer.
MOLECULES, 28 (6).
2452-.
Abstract
The naphthalene diimide compound QN-302, designed to bind to G-quadruplex DNA sequences within the promoter regions of cancer-related genes, has high anti-proliferative activity in pancreatic cancer cell lines and anti-tumor activity in several experimental models for the disease. We show here that QN-302 also causes downregulation of the expression of the <i>S100P</i> gene and the S100P protein in cells and in vivo. This protein is well established as being involved in key proliferation and motility pathways in several human cancers and has been identified as a potential biomarker in pancreatic cancer. The <i>S100P</i> gene contains 60 putative quadruplex-forming sequences, one of which is in the promoter region, 48 nucleotides upstream from the transcription start site. We report biophysical and molecular modeling studies showing that this sequence forms a highly stable G-quadruplex in vitro, which is further stabilized by QN-302. We also report transcriptome analyses showing that <i>S100P</i> expression is highly upregulated in tissues from human pancreatic cancer tumors, compared to normal pancreas material. The extent of upregulation is dependent on the degree of differentiation of tumor cells, with the most poorly differentiated, from more advanced disease, having the highest level of <i>S100P</i> expression. The experimental drug QN-302 is currently in pre-IND development (as of Q1 2023), and its ability to downregulate S100P protein expression supports a role for this protein as a marker of therapeutic response in pancreatic cancer. These results are also consistent with the hypothesis that the <i>S100P</i> promoter G-quadruplex is a potential therapeutic target in pancreatic cancer at the transcriptional level for QN-302.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | pancreatic cancer, quadruplex, biophysics, S100P, transcriptome, MIA PaCa-2 xenograft, molecular modeling |
| Divisions: | Faculty of Health and Life Sciences Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology |
| Depositing User: | Symplectic Admin |
| Date Deposited: | 19 Apr 2023 10:14 |
| Last Modified: | 19 Apr 2023 18:24 |
| DOI: | 10.3390/molecules28062452 |
| Open Access URL: | https://doi.org/10.3390/molecules28062452 |
| Related URLs: | |
| URI: | https://livrepository.liverpool.ac.uk/id/eprint/3169737 |
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