Hyperthermia switches glucose depletion-induced necrosis to apoptosis in A549 lung adenocarcinoma cells.

Both cellular and clinical studies have shown that hyperthermia is one of the most potent sensitizers for the action of ionizing radiation. Although hyperthermic improvement in clinical outcome is suggested to be linked to its ability to induce cell cycle arrest and apoptosis, and to activate the immune system and to cause increases in blood flow and tumor oxygenation, the mechanism behind this is still unclear. Previously, we demonstrated that glucose deprivation (GD), a common characteristic of the tumor microenvironment, induced necrosis, which is implicated in tumor progression and aggressiveness, through the production of reactive oxygen species (ROS) in A549 lung carcinoma cells. We examined the effects of heat shock on ROS production and necrosis in response to GD. Here we show that mild, but not harsh, heat shock prevented GD-induced necrosis and switched the cell death mode to apoptosis in A549 cells through the ERK1/2 pathway that could suppress GD-induced CuZnSOD release and ROS production. These results demonstrate that contrary to severe heat shock, mild heat shock has the ability to decrease oxidative stress in cells, thereby causing the cell death mode switch from tumor promoting necrosis to tumor suppressive apoptosis, which may contribute to its anti-neoplastic activities.