Involvement of The Receptor For Advanced Glycation End Products (Rage) In Progression of Pancreatic Cancer

<p>Oncogenic<strong> </strong><em>KRAS</em> is central to several cancer types including pancreatic ductal adenocarcinoma (PDAC), but has been determined to be “undruggable”. Recent studies have indicated that oncogenic <em>KRAS</em> is not constitutively active but relies on a feed-forward stimulatory mechanism involving inflammation. In the current study we investigated the mechanisms by which, the receptor for advanced glycation end products (RAGE) affects and maintains <em>KRAS </em>activity. We observed that RAGE levels were elevated and there was a shift in the levels of specific isoforms upon inflammation in pancreatic cells and PDAC. Furthermore, RAGE agonists were found to increase Ras activity and downstream signaling in a time- and dose-dependent manner. Likewise, inhibition of RAGE decreased Ras signaling activity and downstream signals in multiple PDAC cell lines. In vivo, inhibition of RAGE activity using an antagonist inhibited tumor progression and increased survival rate. These data indicate that RAGE plays a central role in maintaining the activity of oncogenic KRAS and supporting tumor growth. These data raises the possibility of new approaches to inhibit the carcinogenic actions of <em>KRAS </em>indirectly by blocking the mechanisms through which, RAGE maintains its activity.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation (PhD)

Year dc:date.available

2017

Authors dc:creator

• Azizian, Nancy, MS
• <p>0000-0002-1158-0608</p>

Contributors dc:contributor

• Craig Logsdon, Ph.D.
• Bill Mattox, Ph.D.
• Candelaria Gomez-Manzano, MD.

• RAGE
• Erk
• NF-kB
• PanIN
• PDAC
• KRas
• Biology
• Life Sciences
• Medicine and Health Sciences

Repository record dc:identifier

https://digitalcommons.library.tmc.edu/utgsbs_dissertations/748

OAI identifier oai:identifier

oai:digitalcommons.library.tmc.edu:utgsbs_dissertations-1846