PKCδRegulates Translation Initiation through PKR and eIF2αin Response to Retinoic Acid in Acute Myeloid Leukemia Cells

Bulent Ozpolat,S Neslihan Alpay,Magaly Barria,Gabriel Lopez-Berestein,Baki Gezgen,Ugur Akar,Kevin Coombes,Steve Kornblau,Ibrahim Tekedereli,Nianxiang Zhang

doi:10.1155/2012/482905

Bulent Ozpolat, S Neslihan Alpay + Show 8 more

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https://doi.org/10.1155/2012/482905

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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.

Highlights

Differentiation block or arrest is one of the major characteristics of acute myeloid leukemia (AML) [1]
NB4 cells that were treated with All-trans retinoic acid (ATRA) (1 μM) at the indicated time points underwent granulocytic differentiation, as indicated by induction of CD11b and CD11c expression detected by fluorescence-activated cell sorting (FACS) analysis (Figures 1(a), 1(b), and 1(c))
We found that ATRA and arsenic trioxide (ATO) induce PKCδ expression, which is closely correlated with the increased phosphorylation (Ser 51) of eukaryotic translation initiation factor-2α (eIF2α) in NB4 cells by Western blot analysis (Figure 5(a))

Summary

Introduction

Differentiation block or arrest is one of the major characteristics of acute myeloid leukemia (AML) [1]. All-trans retinoic acid (ATRA), an active metabolite of vitamin A, is a potent inducer of cellular differentiation and growth arrest in various tumor cell lines and has been successfully used in the treatment of acute promyelocytic leukemia (APL) [1,2,3,4,5]. The success of ATRA in the treatment of APL introduced the concept of differentiation therapy in treating malignant diseases [1]. Arsenic trioxide (ATO), an FDA approved drug, induces both differentiation and apoptosis in APL and AML cells [5].

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