Targeting stress-induced signaling pathways in pancreatic cancer and vascular disease

Download files
Access & Terms of Use
open access
Embargoed until 2015-11-30
Copyright: Sheahan, Anjali Viswa
Altmetric
Abstract
Cellular stress is a consequence of oncogenic transformation that ultimately results in a highly proliferative cell with malignant potential. Reduced vascular perfusion is a result of the desmoplastic reaction that leads to limited growth-factor and nutrient availability. Conventional anti-cancer therapies such as radiation and cytotoxic administration function by causing DNA damage and are also an insult to the tumor cell. Consequentially, cytotoxic drugs trigger either apoptotic or pro-survival responses and ultimately determine the fate of the tumor cell. Similarly, insults to the vasculature such as atherosclerotic plaque formation and endovascular interventions result in the activation of stress-response pathways in vascular smooth muscle cells (VSMCs). Activation of VSMCs results in a phenotypic transformation such that these cells become highly proliferative, migratory and secrete high levels of extra-cellular matrix. In this thesis, three potential gene targets were examined in the context of pancreatic cancer and vascular disease. We first demonstrate that the transcription factor c-Jun is stress-inducible in pancreatic cancer cells. Loss-of-function studies reveal the importance of this factor to pancreatic cancer cell motility. c-Jun modulates the expression of downstream factors critical to extra-cellular sensing and extra-cellular matrix remodeling. We also explore the potential of c-Jun as a gemcitabine chemo-sensitizer. Targeted inhibition of gemcitabine-inducible c-Jun expression was found to enhance gemcitabine-mediated reductions in pancreatic cancer cell clonogenicity and proliferation. Two factors identified as injury- and FGF-2-inducible in VSMCs may have utility in cancer therapy. Activating transcription factor-4 (ATF4) deficient cells were utilized to demonstrate the role of this gene in platelet-derived growth factor BB-mediated cell migration via the transcriptional regulation of tenascin C. The interaction of YrdC with ribosomal protein L12 was established using Forster resonance energy transfer (FRET) microscopy, confirming its function as a stress-inducible translation factor. Stress-response pathways underpin several critical cellular processes common to cancer and vascular pathogenesis including cell proliferation, survival, migration and extra-cellular remodeling. These findings add to our understanding of these molecular processes and may therefore uncover therapeutic targets of potential value in the treatment of these diseases.
Persistent link to this record
Link to Publisher Version
Link to Open Access Version
Additional Link
Author(s)
Sheahan, Anjali Viswa
Supervisor(s)
Khachigian, Levon
Creator(s)
Editor(s)
Translator(s)
Curator(s)
Designer(s)
Arranger(s)
Composer(s)
Recordist(s)
Conference Proceedings Editor(s)
Other Contributor(s)
Corporate/Industry Contributor(s)
Publication Year
2013
Resource Type
Thesis
Degree Type
PhD Doctorate
UNSW Faculty
Files
download public version.pdf 7.12 MB Adobe Portable Document Format
Related dataset(s)