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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. 

Author information

Cho JH1,2, Hong WG1, Jung YJ2, Lee J3, Lee E4, Hwang SG1, Um HD1, Park JK5.​

1Department of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, 215-4, Gongneung-Dong, Nowon-Gu, Seoul, 139-706, Republic of Korea.

2Department of Biological Sciences, Gangwon National University, Hyoja 2-dong, Chuncheon-si, Gangwon-do, 200-701, Republic of Korea.

3Department of Biological Science, College of Biological Science, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul, 05029, Republic of Korea.

4Musculoskeletal Bio-Organ Center, College of Life Science, Kyung Hee University, 1732 Deogyeongdaero Giheung-gu, Yongin-si, Gyeonggi-do, 446-701, Korea.

5Department 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.