Heat shock protein 90 (Hsp90) is an essential and conserved chaperone, required for the conformational maturation and stability of many signaling kinases. We hypothesized that the functional pleiotropism of Hsp90 can be exploited during pharmacological inhibition causing simultaneous restraint of tumor growth as well as suppression of distant spread. Recognizing the lack of therapeutic options in advanced and metastatic squamous cell carcinomas (SCC) of the uterine cervix as well as the oral cavity, this dual concept was tested in corresponding cell lines and xenografts, and correlated with clinical data on client protein expression. Examination of the cell cycle response to Hsp90 inhibition revealed a G2/M-arrest in a panel of four cervical cancer cell lines and a contribution of abnormal mitosis to apoptosis induction in vitro. Although limited to intraperitoneal application, in vivo evidence of biological activity including heat shock response and decreased client kinase phosphorylation was seen with the geldanamycin derivative 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG). Importantly, focal adhesion kinase (FAK) signaling and associated functional parameters were inhibited by the drug treatment. Functional significance of FAK as a client was confirmed using a molecular model based on FAK-related non-kinase (FRNK) expression. Dependency on FAK appeared to be a requirement for full response to FRNK as well as 17-DMAG, and was observed in the mesenchymal-like cervical cell line SiHa. FAK expression and E-cadherin loss were features found in both cervical and oral malignancies, but absent from normal mucosa of either anatomic site. Particularly high FAK expression was noted in oral SCC with sarcomatoid features. Thus, we conclude that Hsp90 inhibition has potential in the treatment of advanced and metastatic SCC of cervical and oral origin. The further examination of novel Hsp90-targeting compounds as well as strategies focused on other components of the Hsp90 chaperone complex seems warranted.
| Identifer | oai:union.ndltd.org:TORONTO/oai:tspace.library.utoronto.ca:1807/26517 |
| Date | 16 March 2011 |
| Creators | Schwock, Joerg |
| Contributors | Hedley, David |
| Source Sets | University of Toronto |
| Language | en_ca |
| Detected Language | English |
| Type | Thesis |
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