title: Akt inhibitor MK-2206 promotes anti-tumor activity and cell death by modulation of AIF and Ezrin in colorectal cancer.
abstract: BACKGROUND
  There is extensive evidence for the role of aberrant cell survival signaling mechanisms in cancer progression and metastasis. Akt is a major component of cell survival-signaling mechanisms in several types of cancer. It has been shown that activated Akt stabilizes XIAP by S87 phosphorylation leading to survivin/XIAP complex formation, caspase inhibition and cytoprotection of cancer cells. We have reported that TGFβ/PKA/PP2A-mediated tumor suppressor signaling regulates Akt phosphorylation in association with the dissociation of survivin/XIAP complexes leading to inhibition of stress-dependent induction of cell survival.
  
  
  METHODS
  IGF1R-dependent colon cancer cells (GEO and CBS) were used for the study. Effects on cell proliferation and cell death were determined in the presence of MK-2206. Xenograft studies were performed to determine the effect of MK-2206 on tumor volume. The effect on various cell death markers such as XIAP, survivin, AIF, Ezrin, pEzrin was determined by western blot analysis. Graph pad 5.0 was used for statistical analysis. P < 0.05 was considered significant.
  
  
  RESULTS
  We characterized the mechanisms by which a novel Akt kinase inhibitor MK-2206 induced cell death in IGF1R-dependent colorectal cancer (CRC) cells with upregulated PI3K/Akt signaling in response to IGF1R activation. MK-2206 treatment generated a significant reduction in tumor growth in vivo and promoted cell death through two mechanisms. This is the first report demonstrating that Akt inactivation by MK-2206 leads to induction of and mitochondria-to-nuclear localization of the Apoptosis Inducing Factor (AIF), which is involved in caspase-independent cell death. We also observed that exposure to MK-2206 dephosphorylated Ezrin at the T567 site leading to the disruption of Akt-pEzrin-XIAP cell survival signaling. Ezrin phosphorylation at this site has been associated with malignant progression in solid tumors.
  
  
  CONCLUSIONS
  The identification of these 2 novel mechanisms leading to induction of cell death indicates MK-2206 might be a potential clinical candidate for therapeutic targeting of the subset of IGF1R-dependent cancers in CRC.
authors.forename: Ekta
authors.initials: E
authors.lastname: Agarwal
authors.forename: Anathbandhu
authors.initials: A
authors.lastname: Chaudhuri
authors.forename: Premila D
authors.initials: PD
authors.lastname: Leiphrakpam
authors.forename: Katie L
authors.initials: KL
authors.lastname: Haferbier
authors.affiliation: Eppley Cancer Center, University of Nebraska Medical Center, 985950 Nebraska Medical Center, Omaha, Nebraska 68198-5950, USA. mbrattain@unmc.edu.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Brattain
authors.forename: Sanjib
authors.initials: S
authors.lastname: Chowdhury
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D051033:Apoptosis Inducing Factor / Q000235:genetics / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology*; D006801:Humans; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000235:genetics; D034622:RNA Interference; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D000099149:Ezrin
chemical_list: D000970:Antineoplastic Agents; D051033:Apoptosis Inducing Factor; D003598:Cytoskeletal Proteins; D006575:Heterocyclic Compounds, 3-Ring; D051057:Proto-Oncogene Proteins c-akt; D000099149:Ezrin; C548887:MK 2206