Thesis

Assessing the role of JNK in human endothelial cell death induced by anti-cancer therapies

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Awarding institution
  • University of Strathclyde
Date of award
  • 2024
Thesis identifier
  • T17132
Person Identifier (Local)
  • 201976227
Qualification Level
Qualification Name
Department, School or Faculty
Abstract
  • Cardiovascular disease is a common side effect of cancer treatment, particularly in those who have been disease-free for over 10 years. Several studies have shown that radiation and chemotherapeutics, such as Doxorubicin and Cisplatin, can induce cardiovascular disease. Currently, little is understood about the mechanisms behind this phenomenon. The JNK pathway, a key intracellular signalling pathway, has been shown to be activated by both treatment options. Therefore, this could provide a novel target for treatment and prevention. Human Umbilical Vein Endothelial Cells (HUVECs) were exposed to Sunitinib, Doxorubicin, Cisplatin and irradiation kinetic parameters and concentration response curves were established. The effect of these treatments on JNK activation was observed using western blots and cell viability assays. Doxorubicin and Cisplatin were shown to activate JNK, whilst radiation and Sunitinib were found to have no effect on the pathway. Phosphorylation of JNK by Doxorubicin and Cisplatin were found to be delayed and sustained, an observation linked to cell death. FACS analysis then indicated substantial cell damage with an increase in apoptosis and necrosis. Further investigation of the pathway utilised inhibitors, a pharmaceutical inhibitor SP600125, an adenovirus Adv.NLS-1 MKP-2 and CRISPR knockout cell lines. It was shown that the inhibitors did not affect cell viability. However, when investigating a novel cell death mechanism pyroptosis it was found that Adv.NLS-1 MKP-2 reduced LDH levels. It was also observed that this inhibitor reduced pCaspase-3 and GSDME levels, key proteins in pyroptosis. linking JNK to endothelial cell damage. Here it has been observed that Doxorubicin and Cisplatin are linked to JNK activation and cell death. However, the inhibition of JNK did not reduce cell viability indicating further investigation is required to fully understand the phenomenon.
Advisor / supervisor
  • Plevin, Robin
  • Boyd, Marie
Resource Type
DOI

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