Changes in cellular phenotype and resistance to cisplatin in an oral squamous carcinoma model over-expressing cytoglobin

Thorne, Lorna Susan (2016). Changes in cellular phenotype and resistance to cisplatin in an oral squamous carcinoma model over-expressing cytoglobin. University of Birmingham. Ph.D.

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Although cytoglobin is widely considered a tumour suppressor, re-expression plays a role in disease progression in a subset of oral squamous cell carcinomas (OSC), but the mechanism of action is not understood. In this thesis, we developed a new OSC cell model to study the effects of cytoglobin over­ expression on cellular phenotype and resistance to cisplatin. Microarray analysis of cytoglobin­ expressing cells showed significantly altered transcripts related to stress response, adhesion and locomotion, and metabolism. Treatment of cytoglobin-expressing cells with cisplatin revealed a greater response in p53-regulated target expression (MAP3K5, NQOl, CDKN2A and GADD45A) compared to non-expressing cells. Further investigation showed this was associated with higher CHKl, p53 and p21 protein levels, suggesting enhanced activation of p53 signalling pathways. Furthermore, cytoglobin-expressing cells were more resistant to cisplatin-induced apoptosis and altered their cell cycle distribution. These changes were linked to reduced total cellular and mitochondrial superoxide. Collectively, these findings demonstrate for the first time that cytoglobin over- expression is associated with resistance to cisplatin-induced cytotoxicity and the mechanism involves p53 signalling. In conclusion, we propose expression of cytoglobin may afford tumours cells a survival advantage in the harsh environmental conditions of the developing tumour as well as resistance to drugs like cisplatin.

Type of Work: Thesis (Doctorates > Ph.D.)
Award Type: Doctorates > Ph.D.
College/Faculty: Colleges (2008 onwards) > College of Life & Environmental Sciences
School or Department: School of Biosciences
Funders: None/not applicable
Subjects: Q Science > QR Microbiology


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