바로가기  >

Abstract

Protein phosphatase 2A (PP2A) is a ubiquitous multifunctional enzyme usually known as a tumor suppressor. Recent studies have reported that although inhibition of PP2A leads to acceleration of cell growth, it also induces damaged cells to pass through the cell cycle and renders them sensitive to radiotherapy. Here, we investigated the radiosensitizing effects of digoxin as a PP2A inhibitor in two non-small cell lung cancer cell types (H460 and A549) with differential sensitivity to radiation. Digoxin inhibited the proliferation of H460 and A549 cells in a dose-dependent fashion and was especially effective on radioresistant A549 cells. Interestingly, the radiosensitizing effect of digoxin was only present in the radioresistant A549 cells and xenografts. The combination of digoxin and ionizing radiation (IR) significantly reduced clonogenic survival and xenograft tumor growth ( P < 0.001), compared to IR alone. Digoxin suppressed PP2A protein expression and prevented IR-induced PP2A expression in A549 cells. Digoxin treatment combined with IR allowed the damaged cell to progress through the cell cycle via suppression of cell cycle-related proteins (p53, cyclin D1, cyclin B1, CDK4, and p-cdc2). Moreover, digoxin enhanced IR-induced DNA damage through reduction in levels of repair proteins and elevation of p-ATM foci formation up to 24 hours ( P < 0.001). In conclusion, digoxin has a novel function as a PP2A inhibitor, and combined with IR produces a synergistic effect of radiosensitizing cells, thereby indicating a potentially promising therapeutic approach to radioresistant lung cancer treatment. 

Author information

Lee JY1, Kim MS2, Lee MS3, Ju JE3, Chung N4, Jeong YK5.

1Korea Institute of Radiological and Medical Sciences, Seoul, Korea (South), Republic of.2Department of Radiation Oncology, Korea Institute of Radiological and Medical Sciences, Seoul, Korea (South), Republic of.3Radiation Non-clinical Center, Korea Institute of Radiological and Medical Sciences, Seoul, Korea (South), Republic of.4Department of Biosystems Engineering, Korea University, Seoul, Korea (South), Republic of.5Radiation non-clinical center, Korea Institute of Radiological & Medical Science, Seoul, N/A, 01812, Korea (South), Republic of amy3523@kirams.re.kr.