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.
authors.affiliation: 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.
authors.forename: A
authors.initials: A
authors.lastname: Sheth
authors.affiliation: 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.
authors.forename: S
authors.initials: S
authors.lastname: Escobar-Alvarez
authors.affiliation: Molecular Pharmacology and Chemistry Program, Sloan Kettering Institute, New York, NY, USA.
authors.forename: J
authors.initials: J
authors.lastname: Gardner
authors.affiliation: Molecular Pharmacology and Chemistry Program, Sloan Kettering Institute, New York, NY, USA.
authors.forename: L
authors.initials: L
authors.lastname: Ran
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: M L
authors.initials: ML
authors.lastname: Heaney
authors.affiliation: 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.
authors.forename: D A
authors.initials: DA
authors.lastname: Scheinberg
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D002051:Burkitt Lymphoma / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006019:Glycolysis / Q000187:drug effects; D019337:Hematologic Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D006410:Hematopoiesis / Q000187:drug effects; D006801:Humans; D006877:Hydroxamic Acids / Q000633:toxicity; D007951:Leukemia, Myeloid / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology*; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D056811:Unfolded Protein Response / Q000187:drug effects
chemical_list: D006877:Hydroxamic Acids; D016271:Proto-Oncogene Proteins c-myc; D000581:Amidohydrolases; C000597680:peptide deformylase, human; C010531:actinonin