%0 Journal Article
%T PKC¦Ä Regulates Translation Initiation through PKR and eIF2¦Á in Response to Retinoic Acid in Acute Myeloid Leukemia Cells
%A Bulent Ozpolat
%A Ugur Akar
%A Ibrahim Tekedereli
%A S. Neslihan Alpay
%A Magaly Barria
%A Baki Gezgen
%A Nianxiang Zhang
%A Kevin Coombes
%A Steve Kornblau
%A Gabriel Lopez-Berestein
%J Leukemia Research and Treatment
%D 2012
%I Hindawi Publishing Corporation
%R 10.1155/2012/482905
%X Translation initiation and activity of eukaryotic initiation factor-alpha (eIF2¦Á), the rate-limiting step of translation initiation, is often overactivated in malignant cells. Here, we investigated the regulation and role of eIF2¦Á 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 eIF2¦Á, through the induction of protein kinase C delta (PKC¦Ä) and PKR, but not other eIF2¦Á kinases, such as GCN2 and PERK in APL (NB4) and AML cells (HL60, U937, and THP-1). Inhibition of eIF2¦Á 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 eIF2¦Á through PKC¦Ä/PKR axis. PKC¦Ä and p-eIF2¦Á protein expression levels revealed a significant association between the reduced levels of PKC¦Ä ( £¿£¿ = 0 . 0 3 7 8 ) and peIF2 ( £¿£¿ = 0 . 0 0 4 1 ) and relapses in AML patients ( £¿£¿ = 4 7 ). In conclusion, our study provides the first evidence that PKC¦Ä regulates/inhibits eIF2¦Á through induction of PKR in AML cells and reveals a novel signaling mechanism regulating translation initiation. 1. 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¨C5]. 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]. The molecular events that are involved in underlying mechanism of these drugs are not completely elucidated. Understanding the pathways regulating cell proliferation and differentiation may help designing new molecularly targeted therapies in AML. Translation initiation is a highly regulated process of translation in response to cellular stress and mitogenic stimulation [6¨C11]. Increased translation and protein synthesis are associated with cell proliferation and malignant disease [6, 7]. Translational regulation plays a vital role in the expression of oncogenic, and growth-regulatory, differentiation, and
%U http://www.hindawi.com/journals/lrt/2012/482905/