CDK2 differentially controls normal cell senescence and cancer cell proliferation upon exposure to reactive oxygen species

Abstract

Reactive oxygen species modulate cell fate in a context-dependent manner. Sublethal doses of H 2O 2 decreased the level of proliferating cell nuclear antigen (PCNA) in normal cells (including primary human dermal fibroblasts and IMR-90 cells) without affecting cyclin-dependent kinase 2 (CDK2) activity, leading to cell cycle arrest and subsequent senescence. In contrast, exposure of cancer cells (such as HeLa and MCF7 cells) to H 2O 2 increased CDK2 activity with no accompanying change in the PCNA level, leading to cell proliferation. A CDK2 inhibitor, CVT-313, prevented H 2O 2-induced cancer cell proliferation. These results support the notion that the cyclin/CDK2/p21 Cip1/PCNA complex plays an important role as a regulator of cell fate decisions.