Differential role of diphenyleneiodonium, a flavoenzyme inhibitor, on p53-dependent and -independent cell cycle progression

作者：Song Ju Dong; Kim Kang Mi; Kim Koan Hoi; Kim Chi Dae; Kim Jong Min; Yoo Young Hyun; Park Young Chul^*

来源：International Journal of Oncology, 2008, 33(6): 1299-1306.

DOI：10.3892/ijo_00000121

• diphenyleneiodonium
• cell cycle
• p53
• cyclin D1
• ERK activation

We investigated the differential role of diphenyl-eneiodonium (DPI), which is widely used as in inhibitor of NADPH oxidase. on the activation of cell cycle regulators in the cell cycle progression. DPI efficiently blocked the transition from G(0)/G(1) to S phase by serum stimulation in quiescent HCT-116 (wild-type p53) and HL-60 (null p53) cells. Concomitant with G(0)/G(1) arrest, HCT-116 cells treated with DPI resulted in strong and sustained upregulation of p53 and p21. p53- or p21-deficient HCT-116 cells using a small interfering RNA (siRNA) significantly increased the progression into S phase by stimulation of DPI, compared with DPI alone. However. the silencing of p53 resulted in more efficient transition into S phase than the silencing of p21 siRNA and significantly inhibited p21 upregulation by DPI stimulation, Interestingly, brief exposure to DPI did not change p53 expression, but showed transient upregulation of p21 and G(0)/G(1) arrest. These results suggest that p53 upregulation sustains G(0)/G(1) cell cycle arrest and p21 upregulation by DPI stimulation in HCT-116 cells. In HL-60 cells, DPI also induced p21 upregulation in a p53-independent manner and the increase of p21 expression seems to be regulated by DPI-mediated ERK activation. Cyclin D1 expression was not significantly affected by DPI treatment in HCT-116 cells. However, in HL-60 cells, DPI irreversibly impaired cyclin D1 upregulation by serum stimulation and a much greater fraction of cells arrested in G(0)/G(1) was observed in HL-60 cells than in HCT-116 cells at 24 h after brief DPI treatment. These results suggest that cyclin D1 is an important regulatory factor in the inhibition of cell cycle progression by DPI in HL-60 cells.

• 出版日期2008-12