[Role of P27(Kip1) and TGF-beta1 in APL cell apoptosis induced by As(2)O(3)].
The aim of study was to investigate the effects of arsenic trioxide (As(2)O(3)) on cell cycle and apoptosis of APL cells, as well as changes of P27(Kip1), endogenous TGF-beta1, cyclin E and bcl-2, and to explore the relationship between expression of P27(Kip1) and apoptosis induced by As(2)O(3). The apoptosis and cell cycle changes of APL cells treated with As(2)O(3) were detected by morphology and flow cytometry respectively, the protein and mRNA expressions of P27(Kip1), TGF-beta1, cyclin E and BCL-2 were measured by immunohistochemistry and RT-PCR. The results indicated that As(2)O(3) induced APL cell apoptosis in vitro, and cell cycle was arrested at G(1) phase. Apoptotic cells induced by As(2)O(3) 1, 5 and 10 micromol/L for 24 hours were 1.42%, 4.57% and 10.67% respectively; the proportion of apoptotic cells induced by As(2)O(3) of same concentrations for 48 hours increased to 8.92%, 16.07% and 18.90% respectively; the cells induced by As(2)O(3) for 72 hours were mainly in debris. Protein and mRNA expressions of P27(Kip1) and TGF-beta1 of APL cells after treatment with As(2)O(3) increased, accompanying with decrease of cyclin E, bcl-2 protein and mRNA expressions. Apoptotic cells were related to the expressions of P27(Kip1) (r(mRNA) = 0.55, p < 0.05) and TGF-beta1 (r(mRNA) = 0.51, p < 0.05). There was positive correlation between the expression of TGF-beta1 and of P27(Kip1) (r(mRNA) = 0.31, p < 0.05). It is concluded that the apoptosis of APL cells is induced by As(2)O(3), and the cell cycle is arrested at G(1) phase. The expression of P27(Kip1) is closely related to the extent of apoptosis induced by As(2)O(3). Apoptosis of APL cells induced by As(2)O(3) may be caused by up-regulating TGF-beta1 and P27(Kip1), which is antagonistic to cyclin E and BLC-2, leading to arrest of cell cycle at G(1) phase.
Wang
Lei
L
Department of Hematology, The First Affiliated Hospital, China Medical University, Shenyang 110001, Liaoning Province, China.
Li
Yan
Y
Wang
Ping-Ping
PP
Lu
Xiang-Lan
XL
Wang
Bai-Xun
BX
D000293:Adolescent; D000328:Adult; D000368:Aged; D017209:Apoptosis; D000077237:Arsenic Trioxide; D001152:Arsenicals; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism*; D005260:Female; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D010087:Oxides; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D055815:Young Adult
D001152:Arsenicals; C436291:CDKN1B protein, human; D010087:Oxides; D053773:Transforming Growth Factor beta1; D050760:Cyclin-Dependent Kinase Inhibitor p27; D000077237:Arsenic Trioxide