Signalling pathways involved in cancer cell migration towards CXCL8 and CXCL10

Al Assaf, Enana (2020) Signalling pathways involved in cancer cell migration towards CXCL8 and CXCL10. Doctoral thesis, University of East Anglia.

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Abstract

Aim: Chemokines are signalling molecules that mediate the migration of immune cells and are involved in tumour progression, invasion, and metastasis. CXCL8 and CXCL10 are responsible for the recruitment and activation of leukocytes to the site of inflammation. The aberrant expression of CXCL8 or CXCL10 and their receptors was identified in multiple cancer types where they contribute towards cancer progression.The aim of this thesis was to characterise the role of these two chemokines in cancer cell migration and associated cellular morphological changes, as well as identifying the main signalling pathways involved in these processes, which could be utilized as desirable targets for therapeutic intervention to prevent cancer progression.
Methodology: To investigate the migratory effect of CXCL8 and CXCL10 on cancer cell lines, several migration assays were used, such as time-lapse imaging, chemotaxis, wound healing, and Boyden chamber. The expression of the correspondent receptors of both chemokines was observed using immunofluorescence assay. To investigate the downstream signalling pathways involved in the chemokine-induced migration and cytoskeleton rearrangement, a number of small molecule inhibitors were used. The effect on the release of intracellular calcium was also assessed for some of the inhibitors.
Results: We identified a role of CXCL8 and CXCL10 signalling in the migration of THP-1, MDA-MB231, PC3 and MCF-7 cells. Using small molecule inhibitors to target signalling molecules revealed a difference in the pathways utilised by CXCL8 to induce migration in the two cell lines: PC3 and MDA-MB231 cells. The major signalling pathways investigated are Pi3K/AKT, Raf/Rac/MEK/ERK, DOCK1/2/5, FAK/Src, Arp2/3, PKA, PKC, PKD, and β-catenin. Inhibitors like LY294002, AKTi, ZM336372, SL327, PD89059, BS203580, EHT1864, CPYPP, PF562271, Bosutinib, CK666, CID755673 can inhibit the migration of both MDA-MB231 and PC3 cells which could be further investigated as universal inhibitors. Other inhibitors like L779450, FH535, and H89 were cell-type specific. Furthermore, the effect of PKC on the migration and cytoskeleton rearrangement was cell-type and chemokine specific.
Conclusion: In this thesis we confirmed the migratory effect both CXCL8 and CXCL10 have on different cancer cell lines. The signalling pathways involved in the chemokine-induced migration varied between the cell lines. These potential signalling molecules that were identified require further investigation to establish their vitality as potential cancer treatment.

Item Type:	Thesis (Doctoral)
Faculty \ School:	Faculty of Science > School of Pharmacy
Depositing User:	Nicola Veasy
Date Deposited:	06 Oct 2021 14:46
Last Modified:	06 Oct 2021 14:46
URI:	https://ueaeprints.uea.ac.uk/id/eprint/81581
DOI:

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