PIM Kinase Inhibitors Downregulate STAT3Tyr705 Phosphorylation

Abstract

Using a cell-based high-throughput screen designed to detect small chemical compounds that inhibit cell growth and survival, we identified three structurally related compounds, 21A8, 21H7, and 65D4, with differential activity on cancer versus normal cells. Introduction of structural modifications yielded compound M-110, which inhibits the proliferation of prostate cancer cell lines with IC 50 s of 0.6 to 0.9 μmol/L, with no activity on normal human peripheral blood mononuclear cells up to 40 μmol/L. Screening of 261 recombinant kinases and subsequent analysis revealed that M-110 is a selective inhibitor of the PIM kinase family, with preference for PIM-3. The prostate cancer cell line DU-145 and the pancreatic cancer cell line MiaPaCa2 constitutively express activated STAT3 (pSTAT3 , we used PIM-1-, PIM-2-, or PIM-3-specific siRNA and showed that knockdown of PIM-3, but not of PIM-1 or PIM-2, in DU-145 cells results in a significant downregulation of pSTAT3 Tyr705. The phosphorylation of STAT5 on Tyr694 in 22Rv1 cells is not affected by M-110 or SGI-1776, suggesting specificity for pSTAT3 Tyr705 . These results identify a novel role for PIM-3 kinase as a positive regulator of STAT3 signaling and suggest that PIM-3 inhibitors cause growth inhibition of cancer cells by downregulating the expression of pSTAT3 Tyr705

Inhibition of the SOCS1-JAK2-STAT3 Signaling Pathway Confers Neuroprotection in Rats with Ischemic Stroke

“…The SOCS1 pathway could inhibit the kinase activity of JAK2 and abolish the release of associated chemokines by blocking the JAK/STAT pathway, which highlight the negative regulation of SOCS1 on this pathway [13]. Additionally, silencing SOCS3 is essential to suppressing STAT3 phosphorylation, and JAK2/STAT3 expression is down-regulated via inhibition of the JAK2-STAT3 pathway, which is in accordance with our results [29-31]. Similarly, SN could induce Bcl-2 expression by inhibiting the JAK2/STAT3 pathway and prevent apoptosis by blocking the activation of caspase-3 expression, which proves that inhibition of the SOCS1-JAK2-STAT3 signaling pathway could decrease Caspase-3 expression and increase Bcl-2 expression [19].…”

ZFP36 expression impairs glioblastoma cell lines viability and invasiveness by targeting multiple signal transduction pathways

“…38 Ectopic expression of ZFP36 reduces the invasion ability of ln827 cells. Since published data suggest that inhibition of Stat5b reduces the invasion potential of human GBM cells, 29 and that PIM3 kinase inhibitors downregulate STAT3(Tyr705) phosphorylation, 30 thereby impinging on the ability of Stat3 to promote invasion, 31,32 we evaluated whether ectopic expression of ZFP36 is capable of reducing invasion by inducing the downregulation of Stat5b and PIM3 simultaneously. To collect evidences to this regard, we performed wound-healing assays on ln827 ZFP36 and compared them to ln827E.V.…”

“…38 PIM1 and PIM3 are active as oncogenes when their expression increases, owing to a loss of regulation; therefore, it was reasonable to think that by inducing the expression of a gene capable of determining their downregulation, ZFP36, by the hypothesis, would be possible to counteract their oncogenic activity. Among other activities, PIM1 and PIM3 act by repressing apoptosis 30,39,40 and by stimulating the invasion activity of cancer cells. 41 These characteristics are reflected in the gene silencing experiments shown here, where downregulation of PIM1 and PIM3 expression determines cell death and a decrease of invasiveness.…”

Wnt Inhibitor Screen Reveals Iron Dependence of β-Catenin Signaling in Cancers

“…Compound 21H7 was purchased from Ryan Scientific, indirubin-3 0 -monoxime (I3M), desferioxamine, and dimethyloxallyl glycine (DMOG) from Sigma-Aldrich; deferasirox and ciclopirox olamine from ChemPacific Corporation; and M-110 (16), kindly provided by Jan Jongstra (Toronto Western Research Institute, Toronto, ON, Canada), was synthesized by Sundia MediTech Company. OICR142 and OICR623 were synthesized by the OICR Medicinal Chemistry Group.…”