The role of death receptors in ER stress and Inflamation
Citation:O'CONNOR, HAZEL, The role of death receptors in ER stress and Inflamation, Trinity College Dublin.School of Genetics & Microbiology.GENETICS, 2018
Hazel O Connor - MSc Thesis.pdf (MSc Thesis) 7.575Mb
Cell death induced in response to ER stress, particularly in response to classical ER stress-inducing agents thapsigargin, brefeldin A and tunicamycin, has been shown to be dependent on the ER stress-dependent upregulation of the death receptor TRAIL-R2 (DR5) (Lu et al., 2014). ER stress responses have additionally been associated with cytokine production and tumour-associated inflammatory responses. Here we show that ER stress-induced DR5 upregulation contributes to death receptor-dependent inflammatory gene activation and ultimately cytokine production. CRISPR-mediated ablation of the ER stress-associated transcription factor CHOP, death receptors TRAIL-R1 (DR4) and DR5 and death receptor-associated molecule FADD afforded protection from ER stress-associated cytokine production. Overall, these data suggest that TRAIL-R signalling may play a previously unappreciated role in solid tumour-associated, ER stress driven tumour inflammation, immune cell recruitment, angiogenesis and metastasis. Microtubule disruptors paclitaxel (Taxol) and docetaxel (Taxotere) are widely used chemotherapeutic agents that kill rapidly replicating tumour cells. However, these agents also trigger NFB activation and have been associated with metastasis and tumour progression. How these taxanes promote NFB activation and concurrent cytokine production is unknown. Here we implicate an ER stress-associated, TRAIL death receptor-dependent signalling pathway in the induction of inflammatory signalling in response to these agents. More precisely, we show that paclitaxel and docetaxel induce and ER stress response, which ultimately promotes a CHOP-dependent upregulation of the death receptor DR5. Taxane-induced cytokines are dependent on TRAIL death receptors and downstream death receptor-associated signalling molecules FADD and caspase-8. CRISPR-mediated ablation of the aforementioned molecules (CHOP, DR4, DR5, FADD and caspase-8) in HeLa cells afforded protection from taxane-induced cytokine production. Collectively, these data suggest that death receptor-induced inflammatory signatures may contribute to previously observed taxane-associated tumour metastasis and tumour progression.
Author: O'CONNOR, HAZEL
Publisher:Trinity College Dublin. School of Genetics & Microbiology. Discipline of Genetics
Type of material:Thesis
Availability:Full text available