The nongenotoxic carcinogens naphthalene and para-dichlorobenzene suppress apoptosis in Caenorhabditis elegans

Abstract

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.

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Figure 1: Naphthalene and PDCB cause nonheritable apoptosis suppression in C. elegans.
Figure 2: The inhibitory activity of naphthalene and PDCB toward apoptosis in different solvents.
Figure 3: Naphthalene and PDCB suppress apoptosis in different genetic backgrounds and in multiple cell types in C. elegans.
Figure 4: Naphthalene treatment suppresses activated CED-3 (acCED-3)-induced apoptosis in the absence of CED-4.
Figure 5: A naphthalene metabolite, 1,4-naphthoquinone, inhibits the activities of CED-3 and caspase-3 in vitro.
Figure 6: Kinetics of human caspase-3 inactivation by 1,4-naphthoquinone.
Figure 7: vMALDI-LTQ mass spectra of trypsin digests of caspase-3 treated with 1,4-naphthoquinone (1,4-NQ) and mock.

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Acknowledgements

We thank T. Blumenthal, M. Han, M. Stowell, S. Copley and members of the Xue lab for comments and discussions and H.R. Horvitz and P. Sternberg for strains. This work was supported by the US National Institutes of Health R01 grants (GM59083 and GM66262) and a Burroughs Wellcome Fund Career Award (D.X.).

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Correspondence to Ding Xue.

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Kokel, D., Li, Y., Qin, J. et al. The nongenotoxic carcinogens naphthalene and para-dichlorobenzene suppress apoptosis in Caenorhabditis elegans. Nat Chem Biol 2, 338–345 (2006). https://doi.org/10.1038/nchembio791

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