Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.2 (PDK1)
 2,238 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Phosphoinositol-3-kinase (PI3K)/protein kinase B (AKT) and Fms-like tyrosine kinase 3 (FLT3) signaling are aberrantly activated in acute myelogenous leukemia (AML) cells. Constitutively activated AKT and FLT3 regulate leukemia cell survival and resistance to chemotherapy. In this study, we investigated the effects of the novel multiple kinase inhibitor KP372-1 on the survival of AML cell lines and primary AML samples. KP372-1 directly inhibited the kinase activity of AKT, PDK1, and FLT3 in a concentration-dependent manner. Western blot analysis indicated that KP372-1 decreased the phosphorylation of AKT on both Ser(473) and Thr(308); abrogated the phosphorylation of p70S6 kinase, BAD, and Foxo3a via PI3K/AKT signaling; and down-regulated expression of PIM-1 through direct inhibition of FLT3. Treatment of AML cell lines with KP372-1 resulted in rapid generation of reactive oxygen species and stimulation of oxygen consumption, followed by mitochondrial depolarization, caspase activation, and phosphatidylserine externalization. KP372-1 induced pronounced apoptosis in AML cell lines and primary samples irrespective of their FLT3 status, but not in normal CD34(+) cells. Moreover, KP372-1 markedly decreased the colony-forming ability of primary AML samples (IC(50) < 200 nmol/L) with minimal cytotoxic effects on normal progenitor cells. Taken together, our results show that the simultaneous inhibition of critical prosurvival kinases by KP372-1 leads to mitochondrial dysfunction and apoptosis of AML but not normal hematopoietic progenitor cells.
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PMID:Simultaneous inhibition of PDK1/AKT and Fms-like tyrosine kinase 3 signaling by a small-molecule KP372-1 induces mitochondrial dysfunction and apoptosis in acute myelogenous leukemia. 1658

FLT3-ITD is the most frequent tyrosine kinase mutation in acute myeloid leukemia (AML) associated with poor prognosis. We previously found that FLT3-ITD activates the mTORC1/S6K/4EBP1 pathway cooperatively through the STAT5/PIM and PI3K/AKT pathways to promote proliferation and survival by enhancing the eIF4F complex formation required for cap-dependent translation. Here, we show that, in contrast to BCR/ABL causing Ph-positive leukemias, FLT3-ITD distinctively activates the serine/threonine kinases RSK1/2 through activation of the MEK/ERK pathway and PDK1 to transduce signals required for FLT3-ITD-dependent, but not BCR/ABL-dependent, proliferation and survival of various cells, including MV4-11. Activation of the MEK/ERK pathway by FLT3-ITD and its negative feedback regulation by RSK were mediated by Gab2/SHP2 interaction. RSK1 phosphorylated S6RP on S235/S236, TSC2 on S1798, and eIF4B on S422 and, in cooperation with PIM, on S406, thus activating the mTORC1/S6K/4EBP1 pathway and eIF4B cooperatively with PIM. RSK1 also phosphorylated Bad on S75 and downregulated BIM-EL in cooperation with ERK. Furthermore, inhibition of RSK1 increased sensitivities to BH3 mimetics inhibiting Mcl-1 or Bcl-2 and induced activation of Bax, leading to apoptosis, as well as inhibition of proliferation synergistically with inhibition of PIM or PI3K. Thus, RSK1 represents a promising target, particularly in combination with PIM or PI3K, as well as anti-apoptotic Bcl-2 family members, for novel therapeutic strategies against therapy-resistant FLT3-ITD-positive AML.
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PMID:FLT3-ITD Activates RSK1 to Enhance Proliferation and Survival of AML Cells by Activating mTORC1 and eIF4B Cooperatively with PIM or PI3K and by Inhibiting Bad and BIM. 3175 44