Human mitochondrial peptide deformylase, a new anticancer target of actinonin-based antibiotics.
Peptide deformylase activity was thought to be limited to ribosomal protein synthesis in prokaryotes, where new peptides are initiated with an N-formylated methionine. We describe here a new human peptide deformylase (Homo sapiens PDF, or HsPDF) that is localized to the mitochondria. HsPDF is capable of removing formyl groups from N-terminal methionines of newly synthesized mitochondrial proteins, an activity previously not thought to be necessary in mammalian cells. We show that actinonin, a peptidomimetic antibiotic that inhibits HsPDF, also inhibits the proliferation of 16 human cancer cell lines. We designed and synthesized 33 chemical analogs of actinonin; all of the molecules with potent activity against HsPDF also inhibited tumor cell growth, and vice versa, confirming target specificity. Small interfering RNA inhibition of HsPDF protein expression was also antiproliferative. Actinonin treatment of cells led to a tumor-specific mitochondrial membrane depolarization and ATP depletion in a time- and dose-dependent manner; removal of actinonin led to a recovery of the membrane potential consistent with indirect effects on the electron transport chain. In animal models, oral or parenteral actinonin was well tolerated and inhibited human prostate cancer and lung cancer growth. We conclude that HsPDF is a new human mitochondrial enzyme that may provide a novel selective target for anticancer therapy by use of actinonin-based antibiotics.
Department of Molecular Pharmacology and Chemistry, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Mona D
MD
Lee
Yuhong
Y
She
Michael J
MJ
Soskis
Christopher P
CP
Borella
Jeffrey R
JR
Gardner
Paula A
PA
Hayes
Benzon M
BM
Dy
Mark L
ML
Heaney
Mark R
MR
Philips
William G
WG
Bornmann
Francis M
FM
Sirotnak
David A
DA
Scheinberg
D000581:Amidohydrolases / Q000235:genetics / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D002455:Cell Division / Q000502:physiology; D045744:Cell Line, Tumor / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D008564:Membrane Potentials / Q000502:physiology; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology*; D008969:Molecular Sequence Data; D015394:Molecular Structure; D009368:Neoplasm Transplantation; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment; D014183:Transplantation, Heterologous
D000900:Anti-Bacterial Agents; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; D034741:RNA, Small Interfering; D000581:Amidohydrolases; C084507:peptide deformylase; C010531:actinonin