title: Γ-Ionizing radiation-induced activation of the EGFR-p38/ERK-STAT3/CREB-1-EMT pathway promotes the migration/invasion of non-small cell lung cancer cells and is inhibited by podophyllotoxin acetate.
abstract: Here, we report a new intracellular signaling pathway involved in γ-ionizing radiation (IR)-induced migration/invasion and show that podophyllotoxin acetate (PA) inhibits the IR-induced invasion and migration of A549 cells (a non-small cell lung cancer (NSCLC) cell line). Our results revealed that IR increased the invasion/migration of A549 cells, and this effect was decreased by 10 nM PA treatment. PA also inhibited the expressions/activities of matrix metalloprotase (MMP) -2, MMP-9, and vimentin, suggesting that PA could block the IR-induced epithelial-mesenchymal transition (EMT). The IR-induced increases in invasion/migration were associated with the activation of EGFR-AKT, and PA inhibited this effect. P38 and p44/42 ERK were also involved in IR-induced invasion/migration, and combined treatments with PA plus inhibitors of each MAPK synergistically blocked this invasion/migration. In terms of transcription factors (TFs), IR-induced increases in cyclic AMP response element-binding protein-1 (CREB-1) and signal transducer and activator of transcription 3 (STAT3) increased invasion/migration and EMT. PA also inhibited these transcription factors and then blocked IR-induced invasion/migration. Collectively, these results indicate that IR induces cancer cell invasion/migration by activating the EGFR-p38/ERK-CREB-1/STAT3-EMT pathway and that PA blocks this pathway to inhibit IR-induced invasion/migration.
authors.affiliation: Department of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, 215-4, Gongneung-Dong, Nowon-Gu, Seoul, 139-706, Republic of Korea.|Department of Biological Sciences, Gangwon National University, Hyoja 2-dong, Chuncheon-si, Gangwon-do, 200-701, Republic of Korea.
authors.forename: Jeong Hyun
authors.initials: JH
authors.lastname: Cho
authors.affiliation: Department of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, 215-4, Gongneung-Dong, Nowon-Gu, Seoul, 139-706, Republic of Korea.
authors.forename: Wan Gi
authors.initials: WG
authors.lastname: Hong
authors.affiliation: Department of Biological Sciences, Gangwon National University, Hyoja 2-dong, Chuncheon-si, Gangwon-do, 200-701, Republic of Korea.
authors.forename: Yu-Jin
authors.initials: YJ
authors.lastname: Jung
authors.affiliation: Department of Biological Science, College of Biological Science, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul, 05029, Republic of Korea.
authors.forename: Jaeseok
authors.initials: J
authors.lastname: Lee
authors.affiliation: Musculoskeletal Bio-Organ Center, College of Life Science, Kyung Hee University, 1732 Deogyeongdaero Giheung-gu, Yongin-si, Gyeonggi-do, 446-701, Korea.
authors.forename: Eunah
authors.initials: E
authors.lastname: Lee
authors.affiliation: Department of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, 215-4, Gongneung-Dong, Nowon-Gu, Seoul, 139-706, Republic of Korea.
authors.forename: Sang-Gu
authors.initials: SG
authors.lastname: Hwang
authors.affiliation: Department of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, 215-4, Gongneung-Dong, Nowon-Gu, Seoul, 139-706, Republic of Korea.
authors.forename: Hong-Duck
authors.initials: HD
authors.lastname: Um
authors.affiliation: Department of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, 215-4, Gongneung-Dong, Nowon-Gu, Seoul, 139-706, Republic of Korea. jkpark@kirams.re.kr.
authors.forename: Jong Kuk
authors.initials: JK
authors.lastname: Park
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000201:enzymology / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000528:radiation effects; D004354:Drug Screening Assays, Antitumor; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects / Q000528:radiation effects*; D005720:Gamma Rays; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000528:radiation effects; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D008175:Lung Neoplasms / Q000201:enzymology / Q000473:pathology*; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D011034:Podophyllotoxin / Q000031:analogs & derivatives* / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000528:radiation effects*; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000502:physiology
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D047908:Intracellular Signaling Peptides and Proteins; D009363:Neoplasm Proteins; D014157:Transcription Factors; C000613972:podophyllotoxin acetate; D011034:Podophyllotoxin
keywords: Invasion; Migration; NSCLC; Podophyllotoxin acetate; Radiation