Inhibition of Class I Phosphoinositide 3-Kinase Activity Impairs Proliferation and Triggers Apoptosis in Acute Promyelocytic Leukemia without Affecting Atra-Induced Differentiation
ABSTRACT We have investigated the role of phosphoinositide 3-kinases (PI3Ks) in the in vitro pathophysiology of acute promyelocytic leukemia (APL) and in the response to treatment with all-trans-retinoic-acid (ATRA), utilizing a range of novel inhibitors that target individual or all catalytic class I isoforms of PI3K (p110alpha, p110beta, p110delta, and p110gamma). ATRA-induced phosphorylation of the Akt kinase and ribosomal S6 protein in APL cells was sensitive to class I PI3K, and p110beta or p110delta inhibitors, and to the mammalian target of rapamycin (mTOR) inhibitor rapamycin. In primary APL, inhibition of p110beta or p110delta triggered apoptosis in the absence or presence of ATRA. Class I PI3K inhibition could also reverse ATRA-induced protection of these cells against doxorubicin and arsenic trioxide, correlating with impaired induction of the antiapoptotic MCL-1 protein. The differentiation-inducing effects of ATRA were not dependent on class I PI3K/mTOR. In summary, class I PI3K signaling, mediated by p110beta and p110delta, plays an important role in basal and ATRA-induced cell survival mechanisms in APL. Addition of PI3K inhibitors to induction treatment regimens may provide therapeutic benefit.
- SourceAvailable from: Kevin Robert Coombes
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- "This hypothesis remains to be tested by future studies. PI3K/Akt/mTOR signaling pathway is overactivated in APL and AML cells and plays an important role in proliferation , drug resistance, inhibition of apoptosis in cancer cells  . mTOR signaling is a critical inducer of translational activity by phosphorylating 4EBP-1 and releasing eIF4E from 4EBP1 and increasing activity translation initiation complex . "
ABSTRACT: Translation initiation and activity of eukaryotic initiation factor-alpha (eIF2α), the rate-limiting step of translation initiation, is often overactivated in malignant cells. Here, we investigated the regulation and role of eIF2α in acute promyelocytic (APL) and acute myeloid leukemia (AML) cells in response to all-trans retinoic acid (ATRA) and arsenic trioxide (ATO), the front-line therapies in APL. ATRA and ATO induce Ser-51 phosphorylation (inactivation) of eIF2α, through the induction of protein kinase C delta (PKCδ) and PKR, but not other eIF2α kinases, such as GCN2 and PERK in APL (NB4) and AML cells (HL60, U937, and THP-1). Inhibition of eIF2α reduced the expression of cellular proteins that are involved in apoptosis (DAP5/p97), cell cycle (p21Waf1/Cip1), differentiation (TG2) and induced those regulating proliferation (c-myc) and survival (p70S6K). PI3K/Akt/mTOR pathway is involved in regulation of eIF2α through PKCδ/PKR axis. PKCδ and p-eIF2α protein expression levels revealed a significant association between the reduced levels of PKCδ (P = 0.0378) and peIF2 (P = 0.0041) and relapses in AML patients (n = 47). In conclusion, our study provides the first evidence that PKCδ regulates/inhibits eIF2α through induction of PKR in AML cells and reveals a novel signaling mechanism regulating translation initiation.07/2012; 2012:482905. DOI:10.1155/2012/482905
Conference Paper: Transport studies of compact torsatron reactors[Show abstract] [Hide abstract]
ABSTRACT: An efficient transport survey code that uses the spectral collocation method was developed and is being used to study ignition in low-aspect-ratio torsatron reactors. A transport model dominated by helical-ripple-induced neoclassical heat fluxes is used to show that ignition is possible for a range of radial electric fields and plasma aspect ratios even when the loss of trapped alpha particles is considered. However, control of the density profile near the plasma boundary is necessary. The sensitivity of the results to anomalous electron transport is considered. Some initial investigations of the role played by off-diagonal terms in the neoclassical transport matrix in determining reactor performance are also presented, and a potentially attractive operating regime is found when these additional terms are consideredFusion Engineering, 1989. Proceedings., IEEE Thirteenth Symposium on; 11/1989
- PLoS ONE 01/2009; 4(4). DOI:10.1371/journal.pone.0005145.t001 · 3.53 Impact Factor