Poly(ADP-ribose) polymerase inhibitors (PARPi) have received huge attention in oncology over recent years. They are FDA approved for use in BRCA1/2 defective breast and ovarian cancers with absent or dysfunctional homologous recombination repair function. This project builds on novel pilot data demonstrating a novel role of PARP inhibitors disrupting cancer cell bioenergetics.
Our data demonstrates that prostate cell lines, subject to low doses of one such PARPi (Rucaparib), yielded increased cell proliferation by tetrazolium salt assay. Paradoxically, protein content by Sulforhodamine B and nuclear morphology by epifluorescence, indicated cell death via apoptosis. Similar results have been shown in several studies using various cancer cell lines, and some conclude that conflicting results are due to a tetrazolium salt assay-based anomaly. We hypothesise that “increased proliferation” at low doses of Rucaparib likely identifies a metabolic switch from aerobic glycolysis to oxidative phosphorylation. Recent literature has shown that PARP-1 inhibition facilitates upregulated histone deacetylase sirtuin1 activity, via increased nicotinamide adenine dinucleotide (NAD+) availability, consequently culminating in altered mitochondrial bioenergetics.
The role of inflammation in cancer is complex with the need to balance immune cell recruitment with by-stander effect damage. PARP acts as a transcriptional cofactor of Nuclear factor Kappa B (NFκB), transcription factors involved in inflammation and cell survival. The potential anti-inflammatory effect of Rucaparib will be investigated in this project in alarmin based inflammatory cell culture environments.
This project will examine further the effect of Rucaparib on cellular bioenergetics, using a number of in-house assays to conclusively link Rucaparib mediated apoptosis, SIRT1 activity and apoptosis in both primary and relevant cancer cell lines. Additionally the Aglient Seahorse assay system will be utilised to develop novel assays, which we hypothesise, will demonstrate a use for PARP inhibitors, beyond BRCA1/2 mutations, in altering deregulated cellular bioenergetics and overcoming apoptosis resistance; two hallmarks of cancer.
Eligibility and How to Apply:
Please note eligibility requirement:
• Academic excellence of the proposed student i.e. 2:1 (or equivalent GPA from non-UK universities [preference for 1st class honours]); or a Masters (preference for Merit or above); or APEL evidence of substantial practitioner achievement.
• Appropriate IELTS score, if required.
• Applicants cannot apply for this funding if currently engaged in Doctoral study at Northumbria or elsewhere.
For further details of how to apply, entry requirements and the application form, see https://www.northumbria.ac.uk/research/postgraduate-research-degrees/how-to-apply/
Please note: Applications should include a covering letter that includes a short summary (500 words max.) of a relevant piece of research that you have previously completed and the reasons you consider yourself suited to the project. Applications that do not include the advert reference (e.g. SF20/…) will not be considered.
Deadline for applications: 1st July for October start, or 1st December for March start
Start Date: October or March
Northumbria University takes pride in, and values, the quality and diversity of our staff. We welcome applications from all members of the community. The University holds an Athena SWAN Bronze award in recognition of our commitment to improving employment practices for the advancement of gender equality.
For enquiries, contact Dr Hannah Walden ([email protected]
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