Human mitochondrial peptide deformylase, a new anticancer target of actinonin-based antibiotics Journal Article
| Authors: | Lee, M. D.; She, Y.; Soskis, M. J.; Borella, C. P.; Gardner, J. R.; Hayes, P. A.; Dy, B. M.; Heaney, M. L.; Philips, M. R.; Bornmann, W. G.; Sirotnak, F. M.; Scheinberg, D. A. |
| Article Title: | Human mitochondrial peptide deformylase, a new anticancer target of actinonin-based antibiotics |
| Abstract: | 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. |
| Keywords: | controlled study; antibiotic agent; carrier protein; human cell; drug tolerability; cancer growth; antineoplastic agents; cell proliferation; animals; mice; cell division; molecular dynamics; rna, small interfering; antineoplastic activity; enzyme activity; cell line, tumor; anti-bacterial agents; amino acid sequence; molecular sequence data; amino terminal sequence; protein synthesis; enzyme inhibitors; sequence alignment; nucleotide sequence; transplantation, heterologous; hydroxamic acids; lung carcinoma; molecular structure; neoplasm transplantation; tumor growth; actinonin; amidohydrolases; mitochondria; mitochondrion; prostate carcinoma; mammal cell; electron transport; membrane potentials; membrane potential; humans; human; priority journal; article; arylformamidase |
| Journal Title: | Journal of Clinical Investigation |
| Volume: | 114 |
| Issue: | 8 |
| ISSN: | 0021-9738 |
| Publisher: | American Society for Clinical Investigation |
| Date Published: | 2004-10-01 |
| Start Page: | 1107 |
| End Page: | 1116 |
| Language: | English |
| DOI: | 10.1172/jci200422269 |
| PROVIDER: | scopus |
| PMCID: | PMC522256 |
| PUBMED: | 15489958 |
| DOI/URL: | |
| Notes: | J. Clin. Invest. -- Cited By (since 1996):61 -- Export Date: 16 June 2014 -- CODEN: JCINA -- Molecular Sequence Numbers: GENBANK: AAG33973, AAG33980, NP_071736, NP_417745, NP_704619; -- Source: Scopus |
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