title: N-(3-oxo-acyl) homoserine lactone inhibits tumor growth independent of Bcl-2 proteins.
abstract: Pseudomonas aeruginosa produces N-(3-oxododecanoyl)-homoserine lactone (C12) as a quorum-sensing molecule for bacterial communication. C12 has also been reported to induce apoptosis in various types of tumor cells. However, the detailed molecular mechanism of C12-triggerred tumor cell apoptosis is still unclear. In addition, it is completely unknown whether C12 possesses any potential therapeutic effects in vivo. Our data indicate that, unlike most apoptotic inducers, C12 evokes a novel form of apoptosis in tumor cells through inducing mitochondrial membrane permeabilization independent of both pro- and anti-apoptotic Bcl-2 proteins. Importantly, C12 inhibits tumor growth in animals regardless of either pro- or anti-apoptotic Bcl-2 proteins. Furthermore, opposite to conventional chemotherapeutics, C12 requires paraoxonase 2 (PON2) to exert its cytotoxicity on tumor cells in vitro and its inhibitory effects on tumor growth in vivo. Overall, our results demonstrate that C12 inhibits tumor growth independent of both pro- and anti-apoptotic Bcl-2 proteins, and through inducing unique apoptotic signaling mediated by PON2 in tumor cells.
authors.affiliation: Molecular Targets Program, University of Louisville, Louisville, KY 40202, USA.|Institute of Technical Biology and Agriculture Engineering, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui Province, P.R. China, 230031.
authors.forename: Guoping
authors.initials: G
authors.lastname: Zhao
authors.affiliation: Molecular Targets Program, University of Louisville, Louisville, KY 40202, USA.
authors.forename: Aaron M
authors.initials: AM
authors.lastname: Neely
authors.affiliation: Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720, USA.
authors.forename: Christian
authors.initials: C
authors.lastname: Schwarzer
authors.affiliation: Second Hospital of Jilin University, Changchun, Jilin Province, P.R. China, 130041.
authors.forename: Huayi
authors.initials: H
authors.lastname: Lu
authors.affiliation: Molecular Targets Program, University of Louisville, Louisville, KY 40202, USA.
authors.forename: Aaron G
authors.initials: AG
authors.lastname: Whitt
authors.affiliation: Molecular Targets Program, University of Louisville, Louisville, KY 40202, USA.
authors.forename: Nicole S
authors.initials: NS
authors.lastname: Stivers
authors.affiliation: Structural Biology Program, James Graham Brown Cancer Center, Departments of Medicine, Pharmacology and Toxicology, University of Louisville, Louisville, KY 40202, USA.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Burlison
authors.affiliation: Department of Physiology and Biophysics, Rosalind Franklin University of Medicine and Science, North Chicago, IL 60064, USA.
authors.forename: Carl
authors.initials: C
authors.lastname: White
authors.affiliation: Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720, USA.
authors.forename: Terry E
authors.initials: TE
authors.lastname: Machen
authors.affiliation: Molecular Targets Program, University of Louisville, Louisville, KY 40202, USA.
authors.forename: Chi
authors.initials: C
authors.lastname: Li
mesh_terms: D015107:4-Butyrolactone / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D043303:Aryldialkylphosphatase / Q000378:metabolism; D018827:Carcinoma, Lewis Lung / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006714:Homoserine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D007124:Immunoenzyme Techniques; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: C000595707:BCL2 protein, human; C109860:N-(3-oxododecanoyl)homoserine lactone; D019253:Proto-Oncogene Proteins c-bcl-2; D006714:Homoserine; D043303:Aryldialkylphosphatase; C468411:PON2 protein, human; D015107:4-Butyrolactone
keywords: Bak; Bax; Bcl-2; homoserine lactone; tumor