Abstract
Progranulin (PGRN), an autocrine growth factor with tumorigenic roles in a variety of tumors, is a putative survival factor for normal and cancer cells in vitro. However, the fundamental mechanism of PGRN-mediated survival of cancer cells suffering from various kinds of microenvironmental stresses, such as serum deprivation, remains unknown. We show here that serum deprivation decreases the protein level of PGRN in cancer cells. PGRN protects cancer cells against serum deprivation-induced apoptosis, and limits the levels of reactive oxygen species (ROS), maintains the integrity of mitochondria and reduces oxidative damage of protein, lipid and DNA in serum-deprived cancer cells. PGRN encourages the ROS scavenger system evidenced by enhanced superoxide dismutase (SOD), catalase protein expression and activity, elevated GSH/GSSG and NADPH levels and increased phase II detoxification enzymes expression in cancer cells with serum withdraw. The role of PGRN in ROS clearance is mediated by PGRN-stimulated nuclear factor (erythroid-derived 2)-like 2 (NFE2L2)-antioxidant response element (ARE) pathway. Our study suggests an antioxidant mechanism of PGRN in the survival of cancer cells under oxidant stress, and provides a new perspective for the adaptive mechanism of cancer cells to the microenvironmental shortages for cell viability that lead to the other malignant features of cancer.