Antonis E Koromilas

Academic title(s): 


Department of Oncology

Antonis E Koromilas
Contact Information

Lady Davis Institute for Medical Research, Rm 508
Sir Mortimer B. Davis-Jewish General Hospital
3755 Côte-Ste-Catherine Road
Montreal, QC H3T 1E2
Ext. 4994 (lab 1) 5653 (lab 2)
Fax: (514) 340-7576

514-340-8222 Ext 23697
Email address: 
antonis.koromilas [at]
Associate Members
Lady Davis Institute, Jewish General Hospital
Graduate supervision: 



Research Interests

Control of protein synthesis, mRNA translation, environmental stress, tumor suppressor genes, oncogenes, signal transduction, protein phosphorylation, breast, lung and colon cancer, chemotherapeutic drugs.

Research Orientation

Dr. Koromilas lab investigates the translational and signaling properties of the phosphorylation of the α subunit the translation initiation factor eIF2 at serine 51 (eIF2αS51P) in stress responses associated with tumor formation and treatment with chemotherapeutic drugs. We also investigate the cell-autonomous function of the transcription factor Stat1 in the inhibition of oncogenic pathways in tumor cells and regulation of tumor responses to treatments with anti-tumor drugs. We employ human and mouse models of solid (breast, lung, colon) and hematopoietic cancers (CML) to better understand the function of eIF2αS51P and Stat1 in cancer in the hope of developing better therapies to combat cancer.

Project Outlines

eIF2αS51P phosphorylation in cancer formation and treatment

Induction of eIF2αS51P is mediated by a family of four kinases, namely HRI, PKR, GCN2 and PERK, each of which responds to distinct forms of stress (1). eIF2αS51P is a master regulator of stress with important implications in cancer development (1). Induction of eIF2αS51P results in the general inhibition of mRNA translation but at the same time facilitates translation of select mRNAs encoding proteins that facilitate survival and adaptation to stress (1). If the damage caused by stress is severe, then eIF2αS51P programs the elimination of the cells by inducing death (1). Both biological outcomes are in place to protect the host from the deleterious effects of stress.
  My lab has made important contributions to understanding the mechanisms and biological relevance of the cell fate decisions of eIF2αS51P in tumorigenesis. Specifically, we showed that induction of the PKR-eIF2αS51P arm in response to stress induced by double-stranded (ds) RNA, DNA damage, activation of tumor suppressor genes (PTEN) or hypoxic stress is associated with inhibition of cell proliferation and induction of cell death (2-6). On the other hand, activation of the PERK-eIF2αP and/or GCN2-eIF2αP arm(s) in response to oncogenic, oxidative  or metabolic stress is associated with increased survival, tumor development and resistance of tumor cells to chemotherapeutic drugs (2;7-13). We also found that eIF2αS51P acts downs stream of mTOR and substitutes for the loss of Akt/PKB to promote cell survival under stress (11;14).
We currently work on investigating the cell fate decisions of eIF2αS51P in human and mouse models of cancer. We use human cell lines of breast, lung and colon cancer which have been engineered to be deficient in eIF2αS51P by genetic approaches. The tumor cells are examined for the signaling and translational effects of eIF2αS51P deficiency in response to various forms stress as well as for their growth and response to anti-tumor drugs in immunodeficient mice. We also employ established mouse models of lung (K-ras), breast cancer (ErbB2/Neu) and CML disease (Bcr.Abl), which has been further modified to be deficient in eIF2α kinases (PERK or PKR) or eIF2αS51 in the tumorigenic tissues by genetic means in order to determine tumor progression as well as tumor response to treatments with chemotherapeutic drugs.

The anti-tumor function of Stat1 and its implications in anti-cancer therapies

Stat1 is essential for innate immunity by protecting the host from infections with viruses and other pathogens. Stat1 also functions as a tumor suppressor via its ability to induce anti-tumor immune responses and suppress oncogenic signaling in a cell-autonomous manner. Our lab has made important contributions by demonstrating the anti-tumor properties of Stat1 in lung and breast cancer. Specifically, we found that Stat1 acts in a cell-autonomous manner to inhibit tumor formation by activating forms of ras in mouse and human cultured cells as well as in mice subjected to lung cancer formation by carcinogens (15-17). We also found that Stat1 assumes both immune regulatory and tumor cell-specific functions to suppress ErbB2/HER2 signaling and tumorigenesis (18;19).

Our work focuses on the molecular mechanisms utilized by Stat1 to inhibit lung and breast tumorigenesis. We have observed that despite its anti-tumor effects, Stat1 can mediate the induction of pro-survival pathways in established tumors that interfere with treatments with chemotherapeutic drugs (20). We have been developing mouse models of lung cancer in which Stat1 is conditionally inactivated in the tumorigenic tissue in order to understand the role of Stat1 in therapies with anti-tumor drugs.

Selected publications: 


  • Koromilas AE. Roles of the translation initiation factor eIF2α serine 51 phosphorylation in cancer formation and treatment. Biochim Biophys Acta 2015;1849:871-80.
  • Koromilas AE, Mounir Z. Control of oncogenesis by eIF2α phosphorylation: implications in PTEN and PI3K-Akt signaling and tumor treatment. Future Oncol 2013;9:1005-15.
  • Mounir Z, Koromilas AE. Uncovering the PKR pathway's potential for treatment of tumors. Future Oncol 2010;6:643-5.
  • Mounir Z, Krishnamoorthy JL, Robertson GP, Scheuner D, Kaufman RJ, Georgescu MM, Koromilas AE. Tumor suppression by PTEN requires the activation of the PKR-eIF2α phosphorylation pathway. Sci Signal 2009;2:ra85.
  • Peidis P, Papadakis AI, Muaddi H, Richard S, Koromilas AE. Doxorubicin bypasses the cytoprotective effects of eIF2α phosphorylation and promotes PKR-mediated cell death. Cell Death Differ 2011;18:145-54.
  • Papadakis AI, Paraskeva E, Peidis P, Muaddi H, Li S, Raptis L, Pantopoulos K, Simos G, Koromilas AE. eIF2α Kinase PKR modulates the hypoxic response by Stat3-dependent transcriptional suppression of HIF-1α. Cancer Res 2010;70:7820-9.
  • Mounir Z, Krishnamoorthy JL, Wang S, Papadopoulou B, Campbell S, Muller WJ, Hatzoglou M, Koromilas AE. Akt Determines Cell Fate Through Inhibition of the PERK-eIF2α Phosphorylation Pathway. Sci Signal 2011;4:ra62.
  • Muaddi H, Majumder M, Peidis P, Papadakis AI, Holcik M, Scheuner D, Kaufman RJ, Hatzoglou M, Koromilas AE. Phosphorylation of eIF2α at serine 51 is an important determinant of cell survival and adaptation to glucose deficiency. Mol Biol Cell 2010;21:3220-31.
  • Kusio-Kobialka M, Podszywalow-Bartnicka P, Peidis P, Glodkowska-Mrowka E, Wolanin K, Leszak G, Seferynska I, Stoklosa T, Koromilas AE, Piwocka K. The PERK-eIF2α phosphorylation arm is a pro-survival pathway of BCR-ABL signaling and confers resistance to imatinib treatment in chronic myeloid leukemia cells. Cell Cycle 2012;11:4069-78.
  • Rajesh K, Krishnamoorthy JL, Kazimierczak U, Tenkerian C, Papadakis AI, Wang S, Huang S, Koromilas A.E. Phosphorylation of the translation initiation factor eIF2α at serine 51 determines the cell fate decisions of Akt in response to oxidative stress. Cell Death & Disease 2015;6:e1591
  • Rajesh K, Papadakis AI, Kazimierczak U, Peidis P, Wang S, Ferbeyre G, Kaufman RJ, Koromilas AE. eIF2α phosphorylation bypasses premature senescence caused by oxidative stress and pro-oxidant antitumor therapies. Aging (Albany NY) 2013;5:884-901.
  • Peidis P, Papadakis AI, Rajesh K, Koromilas AE. HDAC pharmacological inhibition promotes cell death through the eIF2α kinases PKR and GCN2. Aging (Albany NY) 2010;2:669-77.
  • Krishnamoorthy J, Rajesh K, Mirzajani F, Kesoglidou P, Papadakis AI, Koromilas AE. Evidence for eIF2α phosphorylation-independent effects of GSK2656157, a novel catalytic inhibitor of PERK with clinical implications. Cell Cycle 2014;13:801-6.
  • Tenkerian C, Krishnamoorthy J, Mounir Z, Kazimierczak U, Khoutorsky A, Staschke KA, Kristof AS, Wang S, Hatzoglou M, Koromilas AE. mTORC2 balances Akt activation and eIF2α serine 51 phosphorylation to promote survival under stress. Mol Cancer Res 2015 June 30. pii: molcanres.0184.2015.
  • Wang S, Raven JF, Durbin JE, Koromilas AE. Stat1 phosphorylation determines Ras oncogenicity by regulating p27 kip1. PLoS ONE 2008;3:e3476.
  • Wang S, Koromilas AE. Stat1 is an inhibitor of Ras-MAPK signaling and Rho small GTPase expression with implications in the transcriptional signature of Ras transformed cells. Cell Cycle 2009;8:2070-9.
  • Wang S, Raven JF, Koromilas AE. STAT1 represses Skp2 gene transcription to promote p27Kip1 stabilization in Ras-transformed cells. Mol Cancer Res 2010;8:798-805.
  • Raven JF, Williams V, Wang S, Tremblay ML, Muller WJ, Durbin JE, Koromilas AE. Stat1 is a suppressor of ErbB2/Neu-mediated cellular transformation and mouse mammary gland tumor formation. Cell Cycle 2011;10:794-804.
  • Koromilas AE, Sexl V. The tumor suppressor function of STAT1 in breast cancer. JAKSTAT 2013;2:e23353.
  • Wang S, Patsis C, Koromilas AE. Stat1 stimulates cap-independent mRNA translation to inhibit cell proliferation and promote survival in response to antitumor drugs. Proc Natl Acad Sci U S A 2015;112:E2149-E2155.
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