Involvement of protein phosphatase 2A in arsenic trioxide-induced differentiation and apoptosis of NB4 cells.
Arsenic trioxide (ATO) is known to have concentration-dependent dual effects on acute promyelocytic leukemia (APL) cells, preferentially inducing apoptosis at relatively high concentrations and promoting partial differentiation at low concentrations. Protein phosphatase 2A (PP2A) has been demonstrated to take part in the differentiation and apoptosis of malignant hematological cells induced by commonly used medicines, such as all-transretinoic acid (ATRA), interferon, arsenic sulfide, etc. However, there are almost no data on the role PP2A plays in ATO-induced APL cell differentiation/apoptosis. In this report, our goal was to show that ATO inhibited the proliferation and induced the apoptosis and differentiation of neuroblastoma NB4 cells. Okadaic acid (OKA), a specific inhibitor of protein phosphatase activity, markedly increased these effects of ATO on cells. To further elucidate the regulation of PP2A during ATO-induced differentiation/apoptosis of NB4 cells, we measured the phosphatase activity and protein expression of PP2A. The activity of PP2A in NB4 cells decreased with increasing concentration of ATO. This decrease of PP2A activity appeared to parallel phenotypic and functional changes of NB4 cells. Western blot analysis showed that the levels of the PP2A structural subunit PP2A-A decreased during the course of ATO-induced differentiation/apoptosis, whereas the expression of the B and C subunits of PP2A was relatively unaltered. In conclusion, the decrease of PP2A activity may be involved in ATO-induced apoptosis and differentiation of APL cells, and this decrease is predicted to be related to the repression of PP2A-A subunit expression.
Department of Hematology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China. oy626@sina.com
Jian
J
Ouyang
Xi-hui
XH
Xu
Jun-hao
JH
Chen
Pin-hao
PH
Xie
Yong-quan
YQ
Xia
D017209:Apoptosis / Q000187:drug effects*; D000077237:Arsenic Trioxide; D001152:Arsenicals; D015153:Blotting, Western; D039481:CD11b Antigen / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects*; D002460:Cell Line; D005434:Flow Cytometry; D006801:Humans; D007202:Indicators and Reagents; D009580:Nitroblue Tetrazolium; D019319:Okadaic Acid / Q000494:pharmacology; D010087:Oxides / Q000633:toxicity*; D054648:Protein Phosphatase 2 / Q000378:metabolism*; D013778:Tetrazolium Salts; D013844:Thiazoles
D001152:Arsenicals; D039481:CD11b Antigen; D007202:Indicators and Reagents; D010087:Oxides; D013778:Tetrazolium Salts; D013844:Thiazoles; D019319:Okadaic Acid; D009580:Nitroblue Tetrazolium; D054648:Protein Phosphatase 2; C022616:thiazolyl blue; D000077237:Arsenic Trioxide