Mutations in topoisomerase I as a self-resistance mechanism coevolved with the production of the anticancer alkaloid camptothecin in plants
Mutations in topoisomerase I as a self-resistance mechanism coevolved with the production of the anticancer alkaloid camptothecin in plants
复制标题
DOI：
10.1073/pnas.0801038105
复制
发表时间：
2008-05-06
影响因子：
11.1
通讯作者：
Saito, Kazuki
中科院分区：
文献类型：
--
作者：
Sirikantaramas, Supaart;Yamazaki, Mami;Saito, Kazuki
植物产生多种有毒化合物，这些化合物常被用作抗癌药物。然而，产酸植物对这些有毒代谢物的自我抗性机制尚不清楚。植物来源的抗癌生物碱喜树碱（CPT）通过靶向DNA拓扑异构酶I （Top1）诱导细胞死亡，Top1是催化DNA拓扑变化的酶。我们发现，产CPT的植物，包括喜树（Camptotheca acuminata）、苦参（Ophiorrhiza pumila）和蛇根（Ophiorrhiza liukiuensis），都具有具有抗CPT点突变的top1，这表明内源性毒性代谢物对目标细胞成分的进化有影响。鉴定出3个促进CPT抗性的氨基酸取代：Asn421Lys、Leu530Ile和Asn722Ser（根据人类Top1编号）。722位的取代与在抗cpt的人类癌细胞中发现的相同。迄今为止，在抗cpt的人类癌细胞中尚未发现其他突变；这预测了未来在cpt耐药的人类癌症患者中发生这些突变的可能性。此外，对产CPT和非产CPT植物top15的比较分析表明，产CPT的植物在CPT生物合成进化之前就已经部分具备了对CPT的抗性。我们的研究结果证明了CPT生产系统对内源性有毒化合物的自我抗性的分子机制，以及生产植物中CPT生产系统与其目标Top1之间的适应性协同进化的可能性。
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.