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
- 448 Downloads
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.
KeywordsRadiation Podophyllotoxin acetate Invasion Migration NSCLC
This work was supported by a grant from the Nuclear Research & Development Program of the National Research Foundation of Korea (NRF), which is funded by the Korean government (MEST; 2012M2A2A7010422), and by the Basic Science Research Program of the NRF (NRF-2014R1A1A2054985).
Compliance with ethical standards
Conflicts of interest
- 4.Park CM, Park MJ, Kwak HJ, Lee HC, Kim MS, Lee SH, et al. Ionizing radiation enhances matrix metalloproteinase-2 secretion and invasion of glioma cells through Src/epidermal growth factor receptor-mediated p38/Akt and phosphatidylinositol 3-kinase/Akt signaling pathways. Cancer Res. 2006;66:8511–9.CrossRefPubMedGoogle Scholar
- 11.Park JK, Jung HY, Park SH, Kang SY, Yi MR, Um HD, et al. Combination of PTEN and gamma-ionizing radiation enhances cell death and G(2)/M arrest through regulation of AKT activity and p21 induction in non-small-cell lung cancer cells. Int J Radiat Oncol Biol Phys. 2008;70:1552–60.CrossRefPubMedGoogle Scholar