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Increased gadd153 Messenger RNA Level Is Associated with Apoptosis in Human Leukemic Cells Treated with Etoposide¹

Laboratory of Oncohematology and Pharmacology, CJF INSERM 94-08, UFR of Medicine/Pharmacy, 7, boulevard Jeanne d'Arc, 21033 Dijon [B. E., L. D., E. S.], and CJF INSERM 95-03, Centre Claudius Regaud, 31000 Toulouse [M. A.], France

Treatment of leukemic cells with topoisomerase inhibitors can lead to growth arrest and subsequent apoptotic cell death. The relationships between cell cycle regulation and apoptosis triggering remain poorly understood. The gadd153 gene encodes the nuclear protein CHOP 10 that acts as a negative modulator of CCAAT/enhancer binding protein transcriptional factors and inhibits cell cycle progression. We have investigated the relationships between gadd153 gene expression and apoptosis induction in four human leukemic cell lines with different sensitivities to apoptosis induced by etoposide (VP-16), a topoisomerase II inhibitor. The gadd153 gene was constitutively expressed in the four studied cell lines. In U937 and HL-60 cells that were very sensitive to apoptosis induction by the drug, VP-16 induced a time- and dose-dependent increase of gadd153 gene mRNA expression. Using agarose gel electrophoresis and a quantitative filter elution assay, apoptotic DNA fragmentation was observed to begin when gadd153 gene expression increased. Equitoxic doses of VP-16 (as defined using a 96-h 3-4,5-dimethylthiazol-2,5-diphenyltetrazolium bromide assay) did not increase the gadd153 mRNA level in K562 and KCL22 cell lines that were more resistant to apoptosis induction by the drug. Nuclear run-on and mRNA stability experiments demonstrated that VP-16 treatment increased gadd153 gene transcription in the sensitive U937 cells. Cycloheximide did not prevent gadd153 expression increase. Both gadd153 mRNA level increase and internucleosomal DNA fragmentation were inhibited by N-tosyl-L-phenylalanine chloromethylketone, a serine threonine protease inhibitor, N-acetyl-leucyl-leucyl-norleucinal, an inhibitor of calpain, N-acetylcysteine, an inhibitor of oxidative metabolism, and overexpression of Bcl-2. Z-VAD and Z-DEVD peptides that inhibit interleukin 1ß-converting enzyme-like proteases suppressed DNA fragmentation without preventing gadd153 mRNA increase in VP-16-treated U937 cells. These results indicate that gadd153 gene expression increase occurs downstream of events sensitive to N-tosyl-L-phenylalanine chloromethylketone, calpain inhibitor, I, and Bcl-2 and upstream of interleukin 1ß-converting enzyme-related proteases activation in leukemic cells in which treatment with VP-16 induces rapid apoptosis.

¹ This work was supported by grants from the Ligue Bourguignonne Contre le Cancer, Ligue de Saône et Loire Contre le Cancer, and the Conseil Régional de Bourgogne.

² To whom requests for reprints should be addressed. Phone: 33-03-80-39-32-26; Fax: 33-03-80-29-36-05.

Received 6/24/96. Accepted 12/20/96.

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