ZINC4085554 inhibits cancer cell adhesion by interfering with the interaction of Akt1 and FAK

  • Authors:
    • Shyam K. More
    • Emilie E. Vomhof‑Dekrey
    • Marc D. Basson
  • View Affiliations

  • Published online on: March 27, 2019     https://doi.org/10.3892/ol.2019.10192
  • Pages: 5251-5260
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Abstract

Perioperative or circulatory forces enhance disseminated cancer cell adhesiveness by modulating focal adhesion kinase (FAK)‑Akt1 interaction. Selectively blocking FAK‑Akt1 interaction by a peptide derived from the FAK‑Four‑point‑one, ezrin, radixin, moesin (FERM) domain reduces colon cancer cell adhesion in vitro and in mice. A preliminary in silico screening identified two small molecules resembling a peptide that may inhibit pressure‑stimulated SW620 cancer cell adhesion to collagen I. The present study selected ZINC4085554 for further study to validate its proposed mechanism of action, using human SW620 colon cancer cells as a model system. At 25 and 50 µM, ZINC4085554 inhibited the pressure‑stimulated adhesion of SW620 colon cancer cells to collagen I. This molecule prevented pressure‑stimulated FAK‑Tyr‑397 phosphorylation; however, it did not affect Akt1‑Ser‑473 phosphorylation, indicating that ZINC4085554 acts downstream of Akt1, while Akt‑Thr‑308 remains unchanged in the presence of pressure and or ZINC4085554. Indeed, ZINC4085554 inhibited FAK‑Akt1 interaction in response to increased extracellular pressure, consistent with the proposed mechanism. ZINC4085554 did not inhibit FAK‑Tyr‑397 phosphorylation in response to cell adhesion to collagen I, indicating the specificity of the inhibitory effects towards force‑stimulated pathways. Finally, the present study confirmed that ZINC4085554 at 50 µM prevented pressure‑activation of adhesion to surgical wounds in vivo in parallel to its ablation of intracellular signaling. In summary, ZINC4085554 is a small molecule mimicking part of the structure of FAK that reduces cancer cell adhesion by impairing pressure‑stimulated FAK‑Akt1 interaction and its downstream consequences. ZINC4085554 does not inhibit conventional outside‑in FAK signaling and may be less toxic than global FAK inhibitors, and ZINC4085554 may be an important step towards the inhibition of metastasis.

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APA
More, S.K., Vomhof‑Dekrey, E.E., & Basson, M.D. (2019). ZINC4085554 inhibits cancer cell adhesion by interfering with the interaction of Akt1 and FAK. Oncology Letters, 17, 5251-5260. https://doi.org/10.3892/ol.2019.10192
MLA
More, S. K., Vomhof‑Dekrey, E. E., Basson, M. D."ZINC4085554 inhibits cancer cell adhesion by interfering with the interaction of Akt1 and FAK". Oncology Letters 17.6 (2019): 5251-5260.
Chicago
More, S. K., Vomhof‑Dekrey, E. E., Basson, M. D."ZINC4085554 inhibits cancer cell adhesion by interfering with the interaction of Akt1 and FAK". Oncology Letters 17, no. 6 (2019): 5251-5260. https://doi.org/10.3892/ol.2019.10192