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Fezovich, Alexander (2023) The response of survivin to hypoxia and the functional roles of its subcellular pools. PhD thesis, University of Nottingham.

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Abstract

Survivin is a highly conserved and multifaceted protein with well characterised roles in mitosis and inhibition of apoptosis. Largely absent from normal adult tissue, survivin is highly expressed in most cancers and is an attractive target for cancer therapeutics. Further evidence has implicated survivin in a number of additional pathways, including cell metabolism, DNA repair and autophagy. These functions are associated with distinct subcellular pools of survivin, located in the cytoplasm, nucleus and mitochondria.

To date, research on survivin has focused on its activity under normoxia. However, solid tumours often establish adverse microenvironmental conditions, characterised by reduced oxygen and nutrient availability. Such conditions are thought to initiate a series of cellular adaptations resulting in altered cell metabolism, elevated treatment resistance and greater tumour aggression. As a protein upregulated by hypoxia and in cancers generally, the contributions of survivin to these adaptations is of great interest. This thesis aims to investigate the potential roles of survivin in hypoxia and further characterise the functional significance of its subcellular pools.

Subcellular fractionation and imaging techniques identified a clear repositioning of survivin from the cell cytoplasm to the mitochondria and nucleus under hypoxia. As these organelles are associated with altered mitochondrial metabolism and increased treatment sensitivity respectively, metabolic and cell survival assays were performed to assess their significance. The specific roles of the subcellular populations were supported by the generation of cell lines expressing survivin constructs targeted to these regions.

Survivin expression in the mitochondria correlated with an increase reliance on glycolysis for ATP production both in normoxia and hypoxia. This appeared to be mediated by upregulation of proteins involved in the glycolytic pathway and inhibition of oxidative phosphorylation, achieved in part by reduced mitochondrial membrane polarisation. A number of potential survivin interactors were identified, establishing various prospective intersections in metabolic pathways through which survivin may operate in cancerous cells.

Forced localisation of survivin to the nucleus has been associated with a loss of apoptosis inhibition and treatment sensitisation. Nuclear survivin has also been associated with DNA damage and may facilitate DNA repair. In contrast to these findings, this thesis reports can inhibit apoptosis under both hypoxia and when forcibly expressed in the nucleus, in a manner independent of DNA repair. This may be mediated by the altered stabilisation of survivin binding partners involved in the regulation of apoptosis and together suggest the utilisation of novel mechanisms to promote survival of cancer cells under hypoxia.

Item Type:	Thesis (University of Nottingham only) (PhD)
Supervisors:	Wheatley, Sally
Keywords:	Survivin, mitosis, apoptosis, DNA repair and autophagy, cytoplasm, mitochondria, cancer therapeutics
Subjects:	Q Science > QH Natural history. Biology R Medicine > RC Internal medicine > RC 254 Neoplasms. Tumors. Oncology (including Cancer)
Faculties/Schools:	UK Campuses > Faculty of Medicine and Health Sciences > School of Life Sciences
Item ID:	71972
Depositing User:	Fezovich, Alexander
Date Deposited:	03 Feb 2023 14:01
Last Modified:	03 Feb 2023 14:01
URI:	https://eprints.nottingham.ac.uk/id/eprint/71972

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