Anticancer drugs affect temperature signaling and epigenetic factors in the cold tolerance of Caenorhabditis elegans

Drugs are vital for maintaining the body healthy and treating diseases. As most drugs have side effects, it is important to gain a complete understanding of their action mechanisms. However, significant cost and time are involved in elucidating their mechanisms. We conducted drug screening at a low cost and in a short time using the phenomenon of cold tolerance in the nematode Caenorhabditis elegans . Among ~ 4000 drugs, we screened the anticancer drugs leptomycin B and camptothecin that affect cold tolerance. Leptomycin B and camptothecin inhibited molecular pathway(s) downstream of the thermosensory signaling via the cGMP-dependent channel TAX-4 in ASJ thermosensory neurons and the thermoreceptor DEG-1 in ASG thermosensory neurons. Leptomycin B affected cold tolerance by inhibiting the molecular pathway upstream of the insulin receptor DAF-2 that regulates cold tolerance in the intestine. Camptothecin decreased the expression levels of genes required for epigenetic processes, such as hrde-1 and deps-1 encoding Argonaute and constitutive P granule protein, respectively. Moreover, hrde-1 and deps-1 mutants exhibited abnormal cold tolerance. This study established an experimental model for drug screening using the cold tolerance of C. elegans and proposed that an anticancer drug upregulates cold tolerance via temperature signaling and epigenetic regulation.