Document Type
Article
Journal Title
Oncotarget
Publication Date
2014
Volume
5
Abstract
Radiation therapy is a staple treatment for pancreatic cancer. However, owing to the intrinsic radioresistance of pancreatic cancer cells, radiation therapy often fails to increase survival of pancreatic cancer patients. Radiation impedes cancer cells by inducing DNA damage, which can activate cell cycle checkpoints. Normal cells possess both a G1 and G2 checkpoint. However, cancer cells are often defective in G1 checkpoint due to mutations/alterations in key regulators of this checkpoint. Accordingly, our results show that normal pancreatic ductal cells respond to ionizing radiation (IR) with activation of both checkpoints whereas pancreatic cancer cells respond to IR with G2/M arrest only. Overexpression/hyperactivation of Rac1 GTPase is detected in the majority of pancreatic cancers. Rac1 plays important roles in survival and Ras-mediated transformation. Here, we show that Rac1 also plays a critical role in the response of pancreatic cancer cells to IR. Inhibition of Rac1 using specific inhibitor and dominant negative Rac1 mutant not only abrogates IR-induced G2 checkpoint activation, but also increases radiosensitivity of pancreatic cancer cells through induction of apoptosis. These results implicate Rac1 signaling in the survival of pancreatic cancer cells following IR, raising the possibility that this pathway contributes to the intrinsic radioresistance of pancreatic cancer.
MeSH Headings
Aminoquinolines, Apoptosis, CDC2 Protein Kinase, Carcinoma, Pancreatic Ductal, Cell Line, Tumor, Cyclin-Dependent Kinases, G2 Phase Cell Cycle Checkpoints, Gamma Rays, Gene Expression Regulation, Neoplastic, Humans, Mutation, Pancreatic Neoplasms, Phosphorylation, Pyrimidines, Radiation Tolerance, Signal Transduction, rac1 GTP-Binding Protein
ISSN
1949-2553
DOI Link
Creative Commons License
This work is licensed under a Creative Commons Attribution 3.0 License.
Recommended Citation
Yan, Y; Hein, Ashley L.; Etekpo, Asserewou; Burchett, Katrina M.; Lin, Chi; Enke, Charles A.; Batra, Surinder K.; Cowan, Kenneth; and Ouellette, Michel M., "Inhibition of RAC1 GTPase Sensitizes Pancreatic Cancer Cells to γ-irradiation" (2014). Journal Articles: Biochemistry & Molecular Biology. 131.
https://digitalcommons.unmc.edu/com_bio_articles/131
Comments
Correction included