Show simple item record

dc.contributor.authorKnox, Henry John Douglas
dc.date.accessioned2022-05-10T16:11:10Z
dc.date.available2022-05-10T16:11:10Z
dc.date.issued2022-05
dc.identifier.urihttp://hdl.handle.net/10675.2/624289
dc.description
dc.description.abstractPancreatic cancer requires elevated protein synthesis. To maintain endoplasmic reticulum (ER) homeostasis, chaperones are overexpressed. Persistent ER stress activates the unfolded protein response (UPR), which can become overwhelmed and lead to cell death. Reactive oxygen species (ROS) from NADPH oxidases (Noxs) can regulate ER homeostasis. In particular, the chaperone protein disulfide-isomerase (PDI) colocalizes with Nox1 in the ER to regulate its activity. Because Nox1 is expressed in the stroma of pancreatic cancer, I studied the extent to which Nox1-derived ROS help establish an adaptive ER homeostasis via PDI in pancreatic cancer cells. I generated a pancreatic cancer mouse model lacking the Nox1 gene in the whole body (Nox1-null KPC mice). Nox1-competent KPC mice were used as a control. The induction of Cre recombination was done by administration of tamoxifen for five consecutive days. After 2 months of tamoxifen induction, the pancreas was harvested. Western blotting was carried out to evaluate PDI, UPR activation, ER stress and cell death. The Nox1-null KPC mice were viable. The lack of Nox1 reduced PDI, C/EBP homologous protein (CHOP) in KPC mice. The UPR sensor IRE1α and the growth arrest and DNA damage-inducible 34 (GADD34) were absent in Nox1-competent KPC mice, but they were recovered in Nox1- null KPC mice. In Nox1-null KPC mice, the apoptotic protein BIM was increased. I concluded that in pancreatic cancer, the lack of Nox1 decreased PDI, which led to an accumulation of unfolded proteins and activation of UPR system. GADD34 recovery increased protein synthesis, worsening the scenario. Persistent ER stress overwhelmed the UPR system, which caused BIM-induced cell death.
dc.publisherAugusta University
dc.subjectMolecular biology
dc.subjectCellular biology
dc.subject
dc.subject
dc.subjectBIM, endoplasmic reticulum homeostasis, NADPH oxidase 1, pancreatic cancer, protein disulfide-isomerase
dc.titleThe Inhibition of NADPH Oxidase 1/Protein Disulfide-Isomerase Increases BIM in Pancreatic Cancer
dc.typedissertationen_US
dc.contributor.departmentBiomedical Sciences
dc.language.rfc3066en
dc.date.updated2022-05-10T16:11:10Z
dc.description.advisorSabbatini, Maria E
dc.description.committeeCsanyi, Gabor
dc.description.committeeSpencer, Angela
dc.description.degreeM.S.
dc.description.embargo05/10/2024


Files in this item

Thumbnail
Name:
Knox_gru_1907M_10261.pdf
Size:
5.610Mb
Format:
PDF

This item appears in the following Collection(s)

Show simple item record