| dc.contributor.author | Singh, Rahul | |
| dc.description.abstract | Pancreatic ductal adenocarcinoma (PDAC) is currently the third leading cause of cancer-related deaths in the US. Although surgery remains the most effective treatment option, only a few PDACs are resectable at diagnosis. Further, only a few PDAC patients respond to conventional chemotherapy making long-term survival notably challenging. Therefore, the identification of novel therapeutic targets is needed to improve PDAC treatment efficacy. Here, we investigated the role of glutathione S-transferase pi-1 (GSTP1) in PDAC pathogenicity. We postulated that a higher expression of GSTP1 provides selective advantages to PDAC cells by scavenging excessive reactive oxygen species (ROS) and promoting survival. Using shRNAs, we knocked down the expression of GSTP1 in metabolically diverse PDAC cells. We show loss of GSTP1 reduces PDAC cell growth and causes oxidative stress. Our results provide evidence that GSTP1 knockdown activates apoptotic signaling by phosphorylating c-Jun N-terminal kinase (JNK) and c-Jun. Further, supporting in vitro data, nude mice bearing orthotopically implanted GSTP1 knockdown PDAC cells showed a significant reduction in tumor size and volume and reduced Ki67 staining.
Further, using multi-omic techniques, we show that GSTP1 knockdown significantly changes the global transcriptomic and proteomic signatures of PDAC cells. Gene set enrichment analyses revealed that cellular metabolism and energy production pathways are most affected in GSTP1 knockdown PDAC cells. Specifically, we report a reduction in the mRNA and protein expression of aldehyde dehydrogenase 7A1 (ALDH7A1) and solute carrier 2A3 (SLC2A3) in GSTP1 knockdown cells compared to the control. We propose that the growth-inhibitory effects of GSTP1 knockdown are due to redox imbalance and impaired energy production pathways. Our data are the first steps of validating GSTP1 as a potential therapeutic target for PDAC. Collectively, our results provide evidence that GSTP1 inhibitors combined with conventional chemotherapy can be an effective treatment for PDAC patients. However, understanding the function of GSTP1 in cancer cell metabolism requires further investigations. Because GSTP1 knockdown affects various metabolic genes, we will evaluate the bioenergetic changes in GSTP1 knockdown PDAC cells. Additionally, comparative evaluation of metabolites and lipids in control and GSTP1 knockdown cells will expand our knowledge of GSTP1 in cancer cell physiology and metabolism. | en_US |
| dc.publisher | North Dakota State University | en_US |
| dc.rights | NDSU policy 190.6.2 | en_US |
| dc.title | Glutathione S-Transferase Pi-1 in Pancreatic Cancer Pathogenesis: Mechanistic Insights Into Its Role in Oxidative Stress, Cell Signaling, and Metabolic Pathways | en_US |
| dc.type | Dissertation | en_US |
| dc.date.accessioned | 2024-01-19T14:46:24Z | |
| dc.date.available | 2024-01-19T14:46:24Z | |
| dc.date.issued | 2021 | |
| dc.identifier.uri | https://hdl.handle.net/10365/33606 | |
| dc.subject | Cancer cell signaling | en_US |
| dc.subject | GSTP1 | en_US |
| dc.subject | Oxidative stress | en_US |
| dc.subject | Pancreatic cancer | en_US |
| dc.subject | Reactive oxygen species | en_US |
| dc.rights.uri | https://www.ndsu.edu/fileadmin/policy/190.pdf | en_US |
| ndsu.degree | Doctor of Philosophy (PhD) | en_US |
| ndsu.college | Interdisciplinary Studies | en_US |
| ndsu.department | Cellular and Molecular Biology | en_US |
| ndsu.program | Cellular and Molecular Biology | en_US |
| ndsu.advisor | Reindl, Katie | |
