Lactate Prevents Glucose Deprivation-Induced Parthanatos in Gastric Cancer Cells Through Alleviating Intracellular Reactive Oxygen Species

Most evidence obtained to date suggests a pivotal role for lactate in the control of tumor growth and metastasis. However, the precise mechanism by which lactate decreases tumor cell death remains incompletely defined. Here, we report that parthanatos, a kind of poly (ADP-ribose) polymerase-1 (PARP1) dependent but caspase-independent programmed cell death, does occur in two gastric Cancer cell lines (MKN28 and MGC803) under glucose-deprived conditions. Lactate prevented the glucose deprivation-induced parthanatos in an acid-independent manner. In addition, glucose deprivation increased intracellular Reactive Oxygen Species (ROS) generation, whereas lactate reduces ROS levels by promoting NADPH generation. AG120, a selective inhibitor of isocitrate dehydrogenase 1 (IDH1) that catalyzes cytosolic NADPH generation, effectively eliminated the effect of lactate on NADPH generation and reversed the protective effect of lactate on glucose deprivation-induced parthanatos. Similar effects were also observed when Lactate Dehydrogenase B (LDHB) was knocked down. Our findings reveal that lactate prevents glucose deprivation-induced parthanatos in gastric Cancer cells by alleviating intracellular oxidative stress, reflecting a new mechanism by which lactate facilitates the adaptation of tumor cells to the nutrient-deficient tumor microenvironment and promotes tumor development.

IDH1; LDHB; lactate; oxidative stress; parthanatos.