Pancreatic cancer has a very poor prognosis, it is the fourth most common cancer worldwide in terms of mortality, and it is expected to be the second most common within a decade. Most patients with pancreatic cancer are either resistante [sic] to chemotherapy or become so, thus surgery is the only choice with a considerable chance of tumour re-growth. Therefore an alternative treatment is urgently sought. The Nuclear Factor Kappa B (NFkB) cascade is comprised of two interdependent pathways, recognized as the classical pathway or canonical NFkB pathway, which is IKKB dependent, and IKKα-dependent non-canonical or alternative NFkB pathway. Studies have linked the hyper-activation of both pathways to pancreatic tumorigenesis. IKKβ inhibitors as a class of potential drugs for anti-cancer treatment have been accompanied by a number of issues regarding toxicity. IKKα has been implicated in a number of biological processes including cancer development, therefore targeting IKKα is a new approach for the development of pancreatic cancer therapies and is examined in this thesis. In chapter three, both NFkB pathways were characterised using different agonists; LTα1β2, TNFα and FCS. LTα1β2 stimulated the IKKα -dependent non-canonical pathway, inducing phosphorylation of p100 after 4h stimulation, while the maximum activation of p52 formation was between 24 and 48h. TNFα and FCS were without effect. TNFα and LTα1β2 stimulated the canonical NFkB pathway and taken together these studies indicated the presence of a functional non-canonical pathway. In chapter four, a number of novel IKKα inhibitors generated in-house, were also examined against both the non-canonical and canonical NFkB pathways. Three different effects were observed; selective inhibition of IKKα by SU1261, SU1411, SU1349, SU1433, SU1438 and 1434. Inhibition of both IKKα and IKKβ by (SU1087, SU1432, SU1499 and SU1436) and no inhibition of either pathway (SU1392).The effect of selective IKKα inhibitors on cell cycle and growth were also examined and confirmed that IKKα has a role in proliferation of pancreatic cancer cells. In chapter five, the expression of IKKα- dependent target genes was investigated using the agonist that activates the IKKα-dependent non-canonical NFkB pathway, LTα1β2. The findings confirmed that the expression of genes (BBC3, EZH2, TNFAIP3, VCAM, MAP3K14 and SERPINB6) was likely to be regulated through this pathway. This was confirmed using IKKα selective inhibitors, which resulted in the expression of all gene subsets were reduced [sic]. Taken together these data indicate that IKKα plays a key role in the regulation of the non-canonical NFkB pathway in pancreatic cancer cells and that selective inhibition IKKα may be a new strategy for developing anti-cancer drugs.
|Date of Award||1 Feb 2017|
- University Of Strathclyde
|Supervisor||Robin Plevin (Supervisor) & Andrew Paul (Supervisor)|