Abstract
Cancer can be cured by platinum-based chemotherapy, but resistance is a major cause of treatment failure. Here we present the nematode Caenorhabditis elegans as a model to study interactions between the platinum drug cisplatin and signaling pathways in vivo. Null mutation in a single gene, asna-1, makes worms hypersensitive to cisplatin. The metalloregulated ATPase ASNA-1 promotes insulin secretion and membrane insertion of tail-anchored proteins. Using structural data from ASNA-1 homologues, we identify specific ASNA-1 mutants that are sensitive to cisplatin while still able to promote insulin signaling. Mutational analysis reveals that hypersensitivity of ASNA-1 mutants to cisplatin remains in absence of CEP-1/p53 or apoptosis. Human ASNA1 can substitute for the worm gene, indicating a conserved function. Cisplatin sensitivity is not affected by decreased insulin signaling in wild-type nematodes or restored insulin signaling in asna-1 mutants. These findings provide a functional insight into ASNA-1, demonstrate that C. elegans can be used to characterize cisplatin resistance mechanisms, and suggest that rationally designed drugs against ASNA-1 can sensitize cancer cells to cisplatin.
Highlights
Mammalian responses to metals have implications in both cancer chemotherapy and environmental toxicology
We observed a significant increase in sensitivity to cisplatin, sodium arsenite, and antimony potassium tartrate in asna-1 larvae compared with wild-type larvae (Table 1)
Worms were injected with asna-1 dsRNA and the progeny arrested in the first larval stage L1 due to absence of ASNA-1–promoted insulin signaling
Summary
Mammalian responses to metals have implications in both cancer chemotherapy and environmental toxicology. Use of the platinum compound cisplatin has improved the outcome for cancer patients for more than 3 decades. Recent development of oxaliplatin for treatment of colon cancer and arsenic trioxide for acute myeloid leukemia has increased the interest in metal complexes [1]. Cisplatin interacts with DNA, resulting in DNA adducts that inhibit both replication and transcription [2]. It induces apoptosis or necrosis in tumor cells whereas dose-limiting side effects occur in non-dividing cells like neurons and nephrons [3]. A combination of cisplatin and a targeted drug for increased tumor sensitivity would improve outcome for cancer patients
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