Inhibition of human mitochondrial peptide deformylase causes apoptosis in c-myc-overexpressing hematopoietic cancers Journal Article

   


Authors: Sheth, A.; Escobar-Alvarez, S.; Gardner, J.; Ran, L.; Heaney, M. L.; Scheinberg, D. A.
Article Title: Inhibition of human mitochondrial peptide deformylase causes apoptosis in c-myc-overexpressing hematopoietic cancers
Abstract: Inhibition of human mitochondrial peptide deformylase (HsPDF) depolarizes the mitochondrial membrane, reduces mitochondrial protein translation and causes apoptosis in Burkitt's lymphoma. We showed that HsPDF mRNA and protein levels were overexpressed in cancer cells and primary acute myeloid leukemia samples. Myc regulates mitochondria and metabolism; we also demonstrated c-myc regulated the expression of HsPDF, likely indirectly. Inhibition of HsPDF by actinonin blocked mitochondrial protein translation and caused apoptotic death of myc-positive Burkitt's lymphoma, but not myc-negative B cells. Inhibition of mitochondrial translation by chloramphenicol or tetracycline, structurally different inhibitors of the mitochondrial ribosome, which is upstream of deformylase activity, followed by treatment with actinonin, resulted in reversal of the biochemical events and abrogation of the apoptosis induced by actinonin. This reversal was specific to inhibitors of HsPDF. Inhibition of HsPDF resulted in a mitochondrial unfolded protein response (increased transcription factors CHOP and CEB/P and the mitochondrial protease Lon), which may be a mechanism mediating cell death. Therefore, HsPDF may be a therapeutic target for these hematopoietic cancers, acting via a new mechanism. © 2014 Macmillan Publishers Limited All rights reserved.
Keywords: controlled study; protein expression; unclassified drug; nonhuman; animal cell; mouse; cell death; apoptosis; enzyme inhibition; animal experiment; animal model; hematologic malignancy; messenger rna; myc protein; cancer cell; tetracycline; peptide deformylase; actinonin; mitochondrial protein; burkitt lymphoma; motility; growth arrest and dna damage inducible protein 153; unfolded protein response; chloramphenicol; extracellular matrix proteins; human mitochondrial peptide deformylase; ccaat enhancer binding protein; priority journal; article; galectin-1; umbilical cord blood derived mesenchymal stem cells; endopeptidase la
Journal Title: Cell Death & Disease
Volume: 5
Issue: 3
ISSN: 2041-4889
Publisher: Nature Publishing Group  
Date Published: 2014-03-27
Start Page: e1152
Language: English
DOI: 10.1038/cddis.2014.112
PROVIDER: scopus
PMCID: PMC3973238
PUBMED: 24675470
DOI/URL:

http://www.scopus.com/inward/record.url?eid=2-s2.0-84897422120&partnerID=40&md5=891f1284a37b22e5bcf81805aaacad5a
Notes: Export Date: 1 May 2014 -- Source: Scopus
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MSK Authors
  1. Mark L Heaney
    94 Heaney
  2. David Scheinberg
    499 Scheinberg
  3. Sindy N Escobar Alvarez
    8 Escobar-Alvarez
  4. Jeffrey Gardner
    34 Gardner
  5. Aneesh Sheth
    5 Sheth
  6. Leili Ran
    20 Ran
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