Antonis E Koromilas

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.