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Roscovitine Inhibits STAT5 Activity and Induces Apoptosis in the Human Leukemia Virus Type 1-Transformed Cell Line MT-2

Department of Interdisciplinary Oncology, H. Lee Moffitt Cancer Center and Research Center, Tampa, Florida, and University of South Florida Medical Center, Tampa, Florida

T cells expressing human leukemia virus (HTLV) type 1, the etiological agent of adult T-cell leukemia, are remarkably resistant to conventional chemotherapy, and the need for drugs that effectively kill these cells is apparent. Here we show that roscovitine, an inhibitor of cyclin-dependent kinases (CDKs), induces the apoptosis of the HTLV-1-transformed T-cell line MT-2. Roscovitine prevented the tyrosine phosphorylation and consequent activation of the transcription factor signal transducer and activator of transcription (STAT) 5 when presented to MT-2 cells in the presence or absence of a caspase-3 inhibitor, and ectopic expression of a dominant-negative form of STAT5 in MT-2 cells induced apoptosis. Roscovitine and dominant-negative STAT5 also reduced the expression of the antiapoptotic protein XIAP, and STAT5 was associated with the XIAP promoter in vivo. Antibody to platelet-derived growth factor (PDGF) receptors coprecipitated STAT5 from extracts of untreated but not roscovitine-treated cells. The tyrosine phosphatase inhibitor sodium orthovanadate ablated the inhibitory effects of roscovitine on STAT5/PDGF receptor interaction, STAT5 activity, and cell survival. We suggest that roscovitine reduces the abundance of tyrosine-phosphorylated PDGF receptors; as a result, STAT5 does not become active, and STAT5 gene products required for cell survival are not expressed.

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