The UPR in cell death and inflammation

Research output: PhD ThesisPhd-Thesis - Research and graduation internal


Cancer cells can adapt under cellular stresses, activating several signaling mechanisms for diverse outcomes. In this PhD thesis, I explored these mechanisms by which cancer cells regulate their pro-survival and pro-death responses in multiple conditions. Lung cancer cells exposed to nutrient starvation, such as glucose or glutamine, revealed pro-survival responses. Starved-cancer cells induce cytokine and chemokine secretion, which in turn affects the tumor microenvironment. I studied the mechanisms behind this phenomenon and found out that glucose-deprived (cancer) cells undergo ER stress, which activates the UPR. The UPR can activate pro-survival responses, such as upregulating multiple cytokines and chemokines, or pro-death outcomes in case of prolonged ER stress. Two important factors that regulate these signalings are ATF4 and ATF6, which are here described to have an antagonistic role in the regulation of glucose deprivation-mediated cell death, TRAIL death receptor induction and cytokine production. Another relevant discovery of this thesis is the link between TRAIL death receptors (DR4 and DR5) and IL-8 in cancer cells. In unstimulated lung cancer cells, these receptors regulate the expression and secretion of IL-8 in a ligand-independent manner. The signalling mechanism involves the NF-κB, ERK-MAPK and Akt pathways. To further characterize the pro-survival and pro-death responses of cancer cells upon cellular stresses, a small panel of B-cell malignancies was studied. Upon ER stresses, these cells show a pro-death outcome which was independent of the TRAIL death receptors, and dependent on Bax/Bak. In conclusion, this PhD thesis tended to characterize the different effects of the UPR in cell death and inflammation in cancer.
Original languageEnglish
QualificationDoctor of Philosophy
Awarding Institution
  • University of Amsterdam
  • Eldering, Eric, Supervisor
  • Muñoz-Pinedo, C., Co-supervisor, External person
Award date17 May 2023
Publication statusPublished - 24 May 2023

Cite this