title: Inhibition of RAC1 GTPase sensitizes pancreatic cancer cells to γ-irradiation.
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.
authors.affiliation: Department of Radiation Oncology, University of Nebraska Medical Center, Omaha, Nebraska, United States of America.
authors.forename: Ying
authors.initials: Y
authors.lastname: Yan
authors.affiliation: Department of Radiation Oncology, University of Nebraska Medical Center, Omaha, Nebraska, United States of America.
authors.forename: Ashley L
authors.initials: AL
authors.lastname: Hein
authors.affiliation: Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska, United States of America.
authors.forename: Asserewou
authors.initials: A
authors.lastname: Etekpo
authors.affiliation: Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska, United States of America.
authors.forename: Katrina M
authors.initials: KM
authors.lastname: Burchett
authors.affiliation: Department of Radiation Oncology, University of Nebraska Medical Center, Omaha, Nebraska, United States of America.
authors.forename: Chi
authors.initials: C
authors.lastname: Lin
authors.affiliation: Department of Radiation Oncology, University of Nebraska Medical Center, Omaha, Nebraska, United States of America.
authors.forename: Charles A
authors.initials: CA
authors.lastname: Enke
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska, United States of America.
authors.forename: Surinder K
authors.initials: SK
authors.lastname: Batra
authors.affiliation: Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska, United States of America.
authors.forename: Kenneth H
authors.initials: KH
authors.lastname: Cowan
authors.affiliation: Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska, United States of America. Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska, United States of America.
authors.forename: Michel M
authors.initials: MM
authors.lastname: Ouellette
mesh_terms: D000634:Aminoquinolines / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D016203:CDC2 Protein Kinase; D021441:Carcinoma, Pancreatic Ductal / Q000473:pathology / Q000532:radiotherapy*; D045744:Cell Line, Tumor; D018844:Cyclin-Dependent Kinases / Q000235:genetics / Q000378:metabolism; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects / Q000235:genetics; D005720:Gamma Rays / Q000627:therapeutic use*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics; D006801:Humans; D009154:Mutation / Q000235:genetics; D010190:Pancreatic Neoplasms / Q000473:pathology / Q000532:radiotherapy*; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics; D011743:Pyrimidines / Q000494:pharmacology; D011836:Radiation Tolerance / Q000187:drug effects / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D020830:rac1 GTP-Binding Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D000634:Aminoquinolines; C487513:NSC 23766; D011743:Pyrimidines; C107953:RAC1 protein, human; D016203:CDC2 Protein Kinase; C528899:CDK1 protein, human; D018844:Cyclin-Dependent Kinases; D020830:rac1 GTP-Binding Protein