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Cell Death Dis. 2014 Mar 27;5:e1152. doi: 10.1038/cddis.2014.112.

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

Author information

1
1] Molecular Pharmacology and Chemistry Program, Sloan Kettering Institute, New York, NY, USA [2] Department of Pharmacology, Weill Graduate School of Biomedical Sciences of Cornell University, New York, NY, USA.
2
Molecular Pharmacology and Chemistry Program, Sloan Kettering Institute, New York, NY, USA.
3
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
4
1] Molecular Pharmacology and Chemistry Program, Sloan Kettering Institute, New York, NY, USA [2] Department of Pharmacology, Weill Graduate School of Biomedical Sciences of Cornell University, New York, NY, USA [3] Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

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.

PMID:
24675470
PMCID:
PMC3973238
DOI:
10.1038/cddis.2014.112
[Indexed for MEDLINE]
Free PMC Article

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