| dc.contributor.author | Dhillon, Harsharan | |
| dc.description.abstract | Piperlongumine (PPLGM), a bioactive agent obtained from long pepper plants, possesses
potent antitumor activity by inducing reactive oxygen species (ROS). However, the mechanisms
for PPLGM’s antitumor actions are not well defined. We investigated PPLGM’s antitumor
effects and molecular mechanisms against pancreatic and colon cancer, two of the leading causes
of cancer death for both men and women in the U.S. We found that PPLGM activated a ROSmediated
DNA damage pathway that lead to pancreatic cancer cell death in vitro. Further, mice
treated with PPLGM showed reduced pancreatic tumor volume, which was associated with a
decrease in tumor cell proliferation and enhanced oxidative stress levels. To elucidate the target
pathways responsible for PPLGM-mediated cell death, RNA sequencing was performed. 684
genes were differentially expressed in pancreatic cancer cells treated with PPLGM compared to
the control. Genes related to ER-stress and UPR pathways were activated in PPLGM-treated
pancreatic cancer cells. To determine the therapeutic efficacy of PPLGM in combination with
currently used chemotherapy in vivo, an orthotopic mouse model of pancreatic cancer was used.
The combination of PPLGM with gemcitabine resulted in greater reduction of tumor weight and
volume than either agent alone, and PPLGM-treated mouse tumors showed decreased expression
of Ki-67, a proliferation marker. In vitro studies supported the in vivo results where the
combination of PPLGM with gemcitabine and erlotinib significantly decreased pancreatic cancer
cell viability and survival, and induced apoptosis compared to control cells or cells treated with
the chemotherapeutic agents alone. PPLGM inhibited the growth of colorectal cancer cells to a
greater degree than normal colon cells and activated p-ERK protein expression. The use of a
MEK inhibitor attenuated the activation of p-ERK and partially blocked PPLGM-mediated cell
death, indicating the involvement of the MEK/ERK pathway in colon cancer cell death. These
results suggest PPLGM holds potential as a therapeutic agent to treat pancreatic and colon cancer
in the clinics. | en_US |
| dc.publisher | North Dakota State University | en_US |
| dc.rights | NDSU policy 190.6.2 | |
| dc.title | Mechanisms of Piperlongumine-Induced Cancer Cell Death | en_US |
| dc.type | Dissertation | en_US |
| dc.type | Video | en_US |
| dc.date.accessioned | 2015-06-19T18:22:40Z | |
| dc.date.available | 2015-06-19T18:22:40Z | |
| dc.date.issued | 2015 | |
| dc.identifier.uri | http://hdl.handle.net/10365/25178 | |
| dc.description.sponsorship | North Dakota State University. Department of Biological Sciences | en_US |
| dc.description.sponsorship | NDSU Graduate School Doctoral Dissertation Fellowship | en_US |
| dc.description.sponsorship | NDSU Center for Protease Research COBRE (NIH 2P20 RR015566, P30 GM103332-01) | en_US |
| dc.description.sponsorship | NDSU Development Foundation Centennial | en_US |
| dc.description.sponsorship | Engebretson Family Research Endowments | en_US |
| dc.rights.uri | https://www.ndsu.edu/fileadmin/policy/190.pdf | |
| ndsu.degree | Doctor of Philosophy (PhD) | en_US |
| ndsu.college | Graduate and Interdisciplinary Studies | en_US |
| ndsu.department | Cellular and Molecular Biology | en_US |
| ndsu.program | Cellular and Molecular Biology | en_US |
| ndsu.advisor | Reindl, Katie | |
