Iodine-125 seed radiation induces ROS-mediated apoptosis, autophagy and paraptosis in human esophageal squamous cell carcinoma cells

Iodine-125 ((125)I) seed brachytherapy has been proven to be a safe and effective treatment for advanced esophageal cancer; however, the mechanisms underlying its actions are not completely understood. In the present study, the anti-cancer mechanisms of (125)I seed radiation in human esophageal squamous cell carcinoma (ESCC) cells (Eca-109 and KYSE-150) were determined, with a particular focus on the mode of cell death. The results showed that (125)I seed radiation significantly inhibited cell proliferation, and induced DNA damage and G2/M cell cycle arrest in both ESCC cell lines. (125)I seed radiation induced cell death through both apoptosis and paraptosis. Eca-109 cells were primarily killed by inducing caspase-dependent apoptosis, with 6 Gy radiation resulting in the largest response. KYSE-150 cells were primarily killed by inducing paraptosis, which is characterized by extensive cytoplasmic vacuolation. (125)I seed radiation induced autophagic flux in both ESCC cell lines, and autophagy inhibition by 3-methyladenine enhanced radiosensitivity. Furthermore (125)I seed radiation induced increased production of reactive oxygen species (ROS) in both ESCC cell lines. Treatment with an ROS scavenger significantly attenuated the effects of (125)I seed radiation on endoplasmic reticulum stress, autophagy, apoptosis, paraptotic vacuoles and reduced cell viability. In vivo experiments showed that (125)I seed brachytherapy induced ROS generation, initiated cell apoptosis and potential paraptosis, and inhibited cell proliferation and tumor growth. In summary, the results demonstrate that in ESCC cells, (125)I seed radiation induces cell death through both apoptosis and paraptosis; and at the same time initiates protective autophagy. Additionally, (125)I seed radiation-induced apoptosis, paraptosis and autophagy was considerably mediated by ROS.