title: Disruption of STAT3 by niclosamide reverses radioresistance of human lung cancer.
abstract: A major challenge affecting the outcomes of patients with lung cancer is the development of acquired radioresistance. However, the mechanisms underlying the development of resistance to therapy are not fully understood. Here, we discovered that ionizing radiation induces phosphorylation of Janus-associated kinase (JAK)-2 and STAT3 in association with increased levels of Bcl2/Bcl-XL in various human lung cancer cells. To uncover new mechanism(s) of radioresistance of lung cancer, we established lung cancer cell model systems with acquired radioresistance. As compared with radiosensitive parental lung cancer cells (i.e., A549, H358, and H157), the JAK2/STAT3/Bcl2/Bcl-XL survival pathway is significantly more activated in acquired radioresistant lung cancer cells (i.e., A549-IRR, H358-IRR, and H157-IRR). Higher levels of STAT3 were found to be accumulated in the nucleus of radioresistant lung cancer cells. Niclosamide, a potent STAT3 inhibitor, can reduce STAT3 nuclear localization in radioresistant lung cancer cells. Intriguingly, either inhibition of STAT3 activity by niclosamide or depletion of STAT3 by RNA interference reverses radioresistance in vitro. Niclosamide alone or in combination with radiation overcame radioresistance in lung cancer xenografts. These findings uncover a novel mechanism of radioresistance and provide a more effective approach to overcome radioresistance by blocking the STAT3/Bcl2/Bcl-XL survival signaling pathway, which may potentially improve lung cancer outcome, especially for those patients who have resistance to radiotherapy.
authors.affiliation: Corresponding Authors: Xingming Deng, Division of Cancer Biology, Department of Radiation Oncology, Emory University School of Medicine and Winship Cancer Institute of Emory University, Atlanta, GA 30322. xdeng4@emory.edu.
authors.forename: Shuo
authors.initials: S
authors.lastname: You
authors.forename: Rui
authors.initials: R
authors.lastname: Li
authors.forename: Dongkyoo
authors.initials: D
authors.lastname: Park
authors.forename: Maohua
authors.initials: M
authors.lastname: Xie
authors.forename: Gabriel L
authors.initials: GL
authors.lastname: Sica
authors.forename: Ya
authors.initials: Y
authors.lastname: Cao
authors.forename: Zhi-Qiang
authors.initials: ZQ
authors.lastname: Xiao
authors.forename: Xingming
authors.initials: X
authors.lastname: Deng
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D006801:Humans; D053614:Janus Kinase 2 / Q000235:genetics; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology / Q000532:radiotherapy; D009534:Niclosamide / Q000008:administration & dosage*; D010766:Phosphorylation / Q000187:drug effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D011836:Radiation Tolerance / Q000187:drug effects*; D011839:Radiation, Ionizing; D011838:Radiation-Sensitizing Agents / Q000008:administration & dosage; D050796:STAT3 Transcription Factor / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects / Q000528:radiation effects; D051020:bcl-X Protein / Q000235:genetics
chemical_list: C494811:BCL2L1 protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; D011838:Radiation-Sensitizing Agents; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D051020:bcl-X Protein; D009534:Niclosamide; C507924:JAK2 protein, human; D053614:Janus Kinase 2