Ismail, Thamir M 
ORCID: 0000-0001-5624-6593, Crick, Rachel G, Du, Min, Shivkumar, Uma, Carnell, Andrew ORCID: 0000-0002-6353-403X, Barraclough, Roger ORCID: 0000-0002-7203-1194, Wang, Guozheng ORCID: 0000-0001-5525-3548, Cheng, Zhenxing, Yu, Weiping, Platt-Higgins, Angela et al (show 2 more authors)
(2023)
Targeted Destruction of S100A4 Inhibits Metastasis of Triple Negative Breast Cancer Cells.
BIOMOLECULES, 13 (7).
1099-.
Abstract
Most patients who die of cancer do so from its metastasis to other organs. The calcium-binding protein S100A4 can induce cell migration/invasion and metastasis in experimental animals and is overexpressed in most human metastatic cancers. Here, we report that a novel inhibitor of S100A4 can specifically block its increase in cell migration in rat (IC<sub>50</sub>, 46 µM) and human (56 µM) triple negative breast cancer (TNBC) cells without affecting Western-blotted levels of S100A4. The moderately-weak S100A4-inhibitory compound, US-10113 has been chemically attached to thalidomide to stimulate the proteasomal machinery of a cell. This proteolysis targeting chimera (PROTAC) RGC specifically eliminates S100A4 in the rat (IC<sub>50</sub>, 8 nM) and human TNBC (IC<sub>50</sub>, 3.2 nM) cell lines with a near 20,000-fold increase in efficiency over US-10113 at inhibiting cell migration (IC<sub>50</sub>, 1.6 nM and 3.5 nM, respectively). Knockdown of S100A4 in human TNBC cells abolishes this effect. When PROTAC RGC is injected with mouse TNBC cells into syngeneic Balb/c mice, the incidence of experimental lung metastases or local primary tumour invasion and spontaneous lung metastasis is reduced in the 10-100 nM concentration range (Fisher's Exact test, <i>p</i> ≤ 0.024). In conclusion, we have established proof of principle that destructive targeting of S100A4 provides the first realistic chemotherapeutic approach to selectively inhibiting metastasis.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | PROTAC destruction, inhibition of migration, metastasis, triple negative breast cancer |
| Divisions: | Faculty of Health and Life Sciences Faculty of Health and Life Sciences > Institute of Infection, Veterinary and Ecological Sciences Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology Faculty of Science and Engineering > School of Physical Sciences |
| Depositing User: | Symplectic Admin |
| Date Deposited: | 12 Jul 2023 13:24 |
| Last Modified: | 05 Aug 2023 04:19 |
| DOI: | 10.3390/biom13071099 |
| Open Access URL: | https://doi.org/10.3390/biom13071099 |
| Related URLs: | |
| URI: | https://livrepository.liverpool.ac.uk/id/eprint/3171652 |
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