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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Abstract

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.

Supervisor(s):