IGF-I enhances cellular senescence via the reactive oxygen species-p53 pathway

Cellular senescence is characterized by growth arrest, enlarged and flattened cell morphology, the expression of senescence-associated beta-galactosidase (SA-beta-gal). and by activation of tumor suppressor networks. Insulin-like growth factor-I (IGF-I) plays a critical role in cellular growth, proliferation, tumorigenesis, and regulation of aging. In the present study, we show that IGF-I enhances cellular senescence in mouse, rat, and human primary cells in the confluent state: IGF-I induced expression of a DNA damage marker, gamma H2AX, the increased levels of p53 and p21 proteins, and activated SA-beta-gal. In the confluent state, an altered downstream signaling of IGF-I receptor was observed. Treatment with a reactive oxygen species (ROS) scavenger, N-acetylcystein (NAC) significantly suppressed induction of these markers. indicating that ROS are involved in the induction of cellular senescence by IGF-I. In p53-null mouse embryonic fibroblasts, the IGF-I-induced augmentation of SA-beta-gal and p21 was inhibited, demonstrating that p53 is required for cellular senescence induced by IGF-I. Thus, these data reveal a novel pathway whereby IGF-I enhances cellular senescence in the ROS and p53-dependent manner and may explain the underlying mechanisms of IGF-I involvement in tumorigenesis and in regulation of aging. (c) 2012 Elsevier Inc. All rights reserved.