Roscovitine inhibits STAT5 activity and induces apoptosis in the human leukemia virus type 1-transformed cell line MT-2.
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) alpha 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 alpha receptor interaction, STAT5 activity, and cell survival. We suggest that roscovitine reduces the abundance of tyrosine-phosphorylated PDGF alpha receptors; as a result, STAT5 does not become active, and STAT5 gene products required for cell survival are not expressed.
Mohapatra
Subhra
S
Department of Interdisciplinary Oncology, H Lee Moffitt Cancer Center and Research Center, Tampa, Florida 33612, USA.
Chu
Baoky
B
Wei
Sheng
S
Djeu
Julie
J
Epling-Burnette
P K
PK
Loughran
Thomas
T
Jove
Richard
R
Pledger
W Jackson
WJ
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D002461:Cell Line, Transformed; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015368:Human T-lymphotropic virus 1 / Q000502:physiology*; D006801:Humans; D008894:Milk Proteins; D011401:Promoter Regions, Genetic; D014176:Protein Biosynthesis; D011506:Proteins / Q000037:antagonists & inhibitors / Q000235:genetics; D011687:Purines / Q000494:pharmacology*; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000037:antagonists & inhibitors / Q000378:metabolism; D000077546:Roscovitine; D050799:STAT5 Transcription Factor; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects* / Q000821:virology; D015534:Trans-Activators / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051636:X-Linked Inhibitor of Apoptosis Protein
D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D008894:Milk Proteins; D011506:Proteins; D011687:Purines; D050799:STAT5 Transcription Factor; D015534:Trans-Activators; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; D000077546:Roscovitine; D020796:Receptor, Platelet-Derived Growth Factor alpha