title: Mutations in topoisomerase I as a self-resistance mechanism coevolved with the production of the anticancer alkaloid camptothecin in plants.
abstract: Plants produce a variety of toxic compounds, which are often used as anticancer drugs. The self-resistance mechanism to these toxic metabolites in the producing plants, however, remains unclear. The plant-derived anticancer alkaloid camptothecin (CPT) induces cell death by targeting DNA topoisomerase I (Top1), the enzyme that catalyzes changes in DNA topology. We found that CPT-producing plants, including Camptotheca acuminata, Ophiorrhiza pumila, and Ophiorrhiza liukiuensis, have Top1s with point mutations that confer resistance to CPT, suggesting the effect of an endogenous toxic metabolite on the evolution of the target cellular component. Three amino acid substitutions that contribute to CPT resistance were identified: Asn421Lys, Leu530Ile, and Asn722Ser (numbered according to human Top1). The substitution at position 722 is identical to that found in CPT-resistant human cancer cells. The other mutations have not been found to date in CPT-resistant human cancer cells; this predicts the possibility of occurrence of these mutations in CPT-resistant human cancer patients in the future. Furthermore, comparative analysis of Top1s of CPT-producing and nonproducing plants suggested that the former were partially primed for CPT resistance before CPT biosynthesis evolved. Our results demonstrate the molecular mechanism of self-resistance to endogenously produced toxic compounds and the possibility of adaptive coevolution between the CPT production system and its target Top1 in the producing plants.
authors.affiliation: Graduate School of Pharmaceutical Sciences, Chiba University, 1-33 Yayoi-cho, Inage-ku, Chiba 263-8522, Japan.
authors.forename: Supaart
authors.initials: S
authors.lastname: Sirikantaramas
authors.forename: Mami
authors.initials: M
authors.lastname: Yamazaki
authors.forename: Kazuki
authors.initials: K
authors.lastname: Saito
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000972:Antineoplastic Agents, Phytogenic / Q000096:biosynthesis* / Q000494:pharmacology; D001665:Binding Sites; D005075:Biological Evolution; D002166:Camptothecin / Q000096:biosynthesis* / Q000494:pharmacology; D004264:DNA Topoisomerases, Type I / Q000737:chemistry / Q000235:genetics*; D004351:Drug Resistance / Q000187:drug effects; D008826:Microbial Sensitivity Tests; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D010802:Phylogeny; D010944:Plants / Q000187:drug effects / Q000201:enzymology*; D012441:Saccharomyces cerevisiae / Q000187:drug effects
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D004264:DNA Topoisomerases, Type I; D002166:Camptothecin