Polo-like kinase-1 (PLK-1) inhibitors as novel therapeutics in oral squamous cell carcinoma

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dc.contributor.advisorBose, Pinaki
dc.contributor.advisorNarendran, Aru
dc.contributor.authorSarkar, Subhanwita
dc.contributor.committeememberBonni, Dr. Shirin
dc.contributor.committeememberChilds, Sarah J.
dc.date2019-11
dc.date.accessioned2019-07-24T14:09:33Z
dc.date.available2019-07-24T14:09:33Z
dc.date.issued2019-07-22
dc.description.abstractPolo-like kinase-1 (PLK-1) belongs to a family of conserved serine/threonine kinases and is an oncogenic protein in many cancers. Therefore, PLK-1 is an attractive therapeutic target and clinical trials are ongoing to test the efficacy of PLK-1 inhibitors in several cancer-types. Oral squamous cell carcinoma (OSCC) is a common head and neck cancer. OSCC is associated with frequent recurrences after initial curative therapy and overall poor prognosis. We analysed RNA sequencing data from The Cancer Genome Atlas (TCGA) and found that PLK-1 mRNA levels are elevated in OSCC compared to normal oral cavity squamous epithelium and high PLK-1 expression in OSCC is associated with worse survival. Based on these results, we tested the efficacy of PLK-1 inhibitors in a panel of ten OSCC cell lines. The PLK-1 inhibitor, volasertib effected cell death at low nanomolar concentrations in most tested OSCC cell lines but not in normal oral keratinocytes. Flowcytometry analysis showed that volasertib induces G2/M arrest in sensitive cell lines. Western blot analysis showed that levels of total PLK-1 and phospho PLK-1 were reduced after volasertib treatment in sensitive cell lines. Volasertib also triggered apoptosis confirmed by the cleavage of PARP and Caspase 3. Cell lines resistant to volasertib did not show any alteration in total PLK-1 and pPLK-1 after volasertib treatment. Post-operative radiotherapy is a common treatment modality in OSCC patients. In two OSCC cell lines that were refractory to volasertib treatment, a combination of volasertib and γ-radiation significantly lowered cell survival compared to volasertib or γ-radiation alone. Combination therapy with γ-radiation and volasertib in resistant cell lines resulted in S-phase arrest. Western blot analysis showed a significant reduction of total PLK-1 and pPLK-1 after combinatorial therapy. Apoptosis was induced in volasertib resistant cells as a result of combination therapy. Taken together, these in vitro studies establish the rationale for further investigation of volasertib efficacy in orthotopic OSCC xenograft models and clinical trials.en_US
dc.identifier.citationSarkar, S. (2019). Polo-like kinase-1 (PLK-1) inhibitors as novel therapeutics in oral squamous cell carcinoma (Master's thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca.en_US
dc.identifier.doihttp://dx.doi.org/10.11575/PRISM/36763
dc.identifier.urihttp://hdl.handle.net/1880/110663
dc.language.isoengen_US
dc.publisher.facultyCumming School of Medicineen_US
dc.publisher.institutionUniversity of Calgaryen
dc.rightsUniversity of Calgary graduate students retain copyright ownership and moral rights for their thesis. You may use this material in any way that is permitted by the Copyright Act or through licensing that has been assigned to the document. For uses that are not allowable under copyright legislation or licensing, you are required to seek permission.en_US
dc.subjectPLK-1en_US
dc.subjecttherapeuticsen_US
dc.subjectoral canceren_US
dc.subject.classificationBiochemistryen_US
dc.titlePolo-like kinase-1 (PLK-1) inhibitors as novel therapeutics in oral squamous cell carcinomaen_US
dc.typemaster thesisen_US
thesis.degree.disciplineMedicine – Biochemistry and Molecular Biologyen_US
thesis.degree.grantorUniversity of Calgaryen_US
thesis.degree.nameMaster of Science (MSc)en_US
ucalgary.item.requestcopytrueen_US
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