Year: 2024
Type: dissertation
Abstract: C-C Chemokine Receptor type 5 (CCR5) is a G-Coupled Protein Receptor, and bound to its main ligand CCL5, the CCR5/CCL5 axis is known to mediate immune responses. The CCL5/CCR5 axis has been found to be associated in multiple diseases including Prostate Cancer (PCa), where it has been postulated to be a target for cancer therapy. Despite published findings that CCR5 antagonist interfere with PCa cells, the transcriptional mechanisms underlying the CCL5/CCR5 axis in PCa are ill defined, especially regarding the genetic and transcriptional regulation of the receptor. The work presented in this thesis focuses on the transcriptional regulation of CCR5 in PCa cell lines, LNCaP and PC3. I investigated whether a long-term cytokine stimulation using CCL5 and/or IL-6 would induce autocrine loops to their respective receptors, activating a cascade of signalling pathways, and whether these cytokines act in synergy at a transcriptional level. My results indicate that, although there is lack of evidence for direct CCL5/CCR5 engagement, long term IL-6 stimulation induced upregulation of STAT3 for LNCaP at the mRNA and protein level, with no differences upon dual IL-6 and CCL5 stimulation. Dual cytokine stimulation increased EIF4EBP1 transcriptional expression in PC3. I also show that long term CCL5 stimulation of LNCaP cells induced transcriptional expression of the CCR5-specific chemokine CCL4 compatible with the idea of a receptor-ligand feedback loop. These findings confirm that although LNCaP and PC3 are models of metastatic PCa, they are vastly different phenotypically and genetically. Further work using cancer cells originating from the tumour microenvironment would be required to confirm my observations and enhance our current understanding of chemokine receptors in cancer biology.
Author: Amran, Ameera Sabrina
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7112131787