The nongenotoxic carcinogens naphthalene and para-dichlorobenzene suppress apoptosis in Caenorhabditis elegans.
Naphthalene (1) and para-dichlorobenzene (PDCB, 2), which are widely used as moth repellents and air fresheners, cause cancer in rodents and are potential human carcinogens. However, their mechanisms of action remain unclear. Here we describe a novel method for delivering and screening hydrophobic chemicals in C. elegans and apply this technique to investigate the ways in which naphthalene and PDCB may promote tumorigenesis in mammals. We show that naphthalene and PDCB inhibit apoptosis in C. elegans, a result that suggests a cellular mechanism by which these chemicals may promote the survival and proliferation of latent tumor cells. In addition, we find that a naphthalene metabolite directly inactivates caspases by oxidizing the active site cysteine residue; this suggests a molecular mechanism by which these chemicals suppress apoptosis. Naphthalene and PDCB are the first small-molecule apoptosis inhibitors identified in C. elegans. The power of C. elegans molecular genetics, in combination with the possibility of carrying out large-scale chemical screens in this organism, makes C. elegans an attractive and economic animal model for both toxicological studies and drug screens.
Kokel
David
D
Department of Molecular, Cellular, and Developmental Biology, University of Colorado, Boulder, Colorado 80309-0347, USA.
Li
Yehua
Y
Qin
Jun
J
Xue
Ding
D
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D017173:Caenorhabditis elegans / Q000187:drug effects*; D029742:Caenorhabditis elegans Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology; D061945:Caspase Inhibitors; D020169:Caspases / Q000187:drug effects / Q000378:metabolism / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D002722:Chlorobenzenes / Q000737:chemistry / Q000494:pharmacology*; D066298:In Vitro Techniques; D015394:Molecular Structure; D009281:Naphthalenes / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D009821:Oils / Q000737:chemistry; D010084:Oxidation-Reduction; D012680:Sensitivity and Specificity; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization / Q000379:methods; D013329:Structure-Activity Relationship
D029742:Caenorhabditis elegans Proteins; D061945:Caspase Inhibitors; D002722:Chlorobenzenes; D009281:Naphthalenes; D009821:Oils; C031721:naphthalene; C018511:4-dichlorobenzene; D020169:Caspases; C089223:ced-3 protein, C elegans