[Specific function of STAT5 in regulation of proliferation of chronic leukemia K562 cells: inhibitory effect of WHI-P131].
In this study, we examined the possible role of JAK/STAT signaling pathway in regulation of proliferation of chronic leukemia cells K562. The thyrosine phosphorylation of STAT3 and STAT5 was used as a marker of an activation status of STAT proteins. We demonstrate that in growing culture of K562 both STAT3 and STAT5 are constitutively activated. To determine the significance of STATs activity in maintaining the high level of K562 proliferation we tested two JAK inhibitors: AG-490 (JAK2 and JAK3 inhibitor) and WHI-P131 (a new specific JAK3 inhibitor). We showed that in long-tern cultures (48 h) of K562 cells with AG-490 or WHI-P132 the cells remain viable. It was found that treatment with WHI-P131 (30-100 microM) decreased the thyrosine phosphorylation of STAT5 being without effect on the high level of STAT3 phosphorylation. In proliferating K562 cells, AG-490 (25-50 microM) did not influence STAT3 and STAT5 phosphorylation. The flow cytometry analysis revealed a dose-dependent decrease in G1 and S phases and an increase in G2/M phases in WHI-P131-treated K562 cell cultures and no changes in cell cycle structure in AG-490-treated cells. Thus, our findings indicate a preferential role for STAT5 (not constitutively active STAT3) in proliferation of leukemia to other JAK drugs which stimulate apoptosis and decrease proliferation, WHI-P131 prevents K562 cells growth by arresting in G2/M phases of cell cycle.
Mitiushova
E V
EV
Aksenov
N D
ND
Marakhova
I I
II
D002455:Cell Division / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D007399:Interphase / Q000187:drug effects; D020014:K562 Cells; D008214:Lymphocytes / Q000187:drug effects / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011799:Quinazolines / Q000494:pharmacology; D050799:STAT5 Transcription Factor / Q000037:antagonists & inhibitors / Q000502:physiology*
D011799:Quinazolines; D050799:STAT5 Transcription Factor; C116180:WHI P131