Open AccessReactive oxygen species‐mediated cyclin D1 degradation mediates tumor growth retardation in hypoxia, independently of p21 cip1 and hypoxia‐inducible factor
Author(s) -
Lim JiHong,
Lee YoonMi,
Chun YangSook,
Park JongWan
Publication year - 2008
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/j.1349-7006.2008.00892.x
Subject(s) - cyclin d1 , cell cycle , ectopic expression , hypoxia (environmental) , cyclin , cell cycle checkpoint , microbiology and biotechnology , cell growth , cancer research , biology , cyclin a , cyclin d , cyclin b , apoptosis , chemistry , cell culture , biochemistry , oxygen , genetics , organic chemistry
Cell growth arrest is an adaptation process for tumor survival in hypoxic environments. As proliferation is a very complicated and dynamic process, hypoxic growth arrest is not considered to be simply determined by a few molecules. Recently, several research groups have demonstrated that hypoxia‐inducible factor (HIF)‐1α plays a crucial role in hypoxia‐induced cell‐cycle arrest by inhibiting c‐Myc and subsequently inducing p21 cip1 expression. However, we found that hypoxic growth arrest could occur even in p21‐null cancer cells, and addressed the p21‐independent process of cell‐cycle arrest. We show that cyclin D1 was downregulated in various cancer cell lines under hypoxic conditions, which was independent of p21 and HIF‐1 and ‐2α expression. It was also found that cyclin D1 was destabilized by the ubiquitin–proteasome system and this degradation process was highly activated by hypoxia. Moreover, antioxidants prevented the hypoxic degradation of cyclin D1 and hydrogen peroxide destabilized cyclin D1 in normoxia. Finally, we demonstrated that ectopic expression of cyclin D1 rescued hypoxic growth arrest in both p21 +/+ and p21 −/– HCT116 cells. Given the results, we here propose that reactive oxygen species‐mediated cyclin D1 degradation contributes to tumor growth retardation in hypoxic environments. ( Cancer Sci 2008; 99: 1798–1805)