[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"detail-sidebar-cat-0-en-105":3,"doc-seo-352041-105":59,"doc-detail-352041-en":131},{"code":4,"msg":5,"data":6},0,"success",[7,13,18,23,28,33,38,43,48,51,55],{"id":8,"doc_module":4,"doc_module_name":9,"category_name":10,"show_sort_weight":11,"slug":12},1,"Document","Story & Novel",90,"story-novel",{"id":14,"doc_module":4,"doc_module_name":9,"category_name":15,"show_sort_weight":16,"slug":17},2,"Literature",80,"literature",{"id":19,"doc_module":4,"doc_module_name":9,"category_name":20,"show_sort_weight":21,"slug":22},4,"Exam",70,"exam",{"id":24,"doc_module":4,"doc_module_name":9,"category_name":25,"show_sort_weight":26,"slug":27},5,"Comic",60,"comic",{"id":29,"doc_module":4,"doc_module_name":9,"category_name":30,"show_sort_weight":31,"slug":32},6,"Technology",50,"technology",{"id":34,"doc_module":4,"doc_module_name":9,"category_name":35,"show_sort_weight":36,"slug":37},7,"Healthcare",40,"healthcare",{"id":39,"doc_module":4,"doc_module_name":9,"category_name":40,"show_sort_weight":41,"slug":42},8,"Research & Report",30,"research-report",{"id":44,"doc_module":4,"doc_module_name":9,"category_name":45,"show_sort_weight":46,"slug":47},9,"Religion & Spirituality",20,"religion-spirituality",{"id":46,"doc_module":4,"doc_module_name":9,"category_name":49,"show_sort_weight":46,"slug":50},"World Cup","world-cup",{"id":52,"doc_module":4,"doc_module_name":9,"category_name":53,"show_sort_weight":52,"slug":54},10,"Lifestyle","lifestyle",{"id":56,"doc_module":4,"doc_module_name":9,"category_name":57,"show_sort_weight":24,"slug":58},19,"General","general",{"code":4,"msg":60,"data":61},"ok",{"site_id":62,"language":63,"slug":64,"title":65,"keywords":66,"description":67,"schema_data":68,"social_meta":124,"head_meta":126,"extra_data":128,"updated_unix":130},105,"en","amitriptyline-inhibits-eag1-channels-by-binding-to-their-pas-domains-and-exerts-eag1-dependent-anti-tumorigenic-effects","Amitriptyline inhibits EAG1 channels by binding to their PAS domains and exerts EAG1-dependent anti-tumorigenic effects","","Ether-a-go-go 1 (EAG1) potassium channels are frequently overexpressed across cancers, and inhibiting their activity reduces tumor growth and migration. The study shows that amitriptyline, a tricyclic antidepressant also used for cancer-related pain management, binds to the PAS domains of EAG1 and suppresses EAG1-mediated anti-tumorigenic signaling. Amitriptyline inhibited growth and migration in EAG1-high MDA-MB-231 and SH-SY5Y cells, with weaker effects in lower EAG1-expressing A375 cells, in vitro and in zebrafish xenografts. Genetic gain- and loss-of-function experiments confirm EAG1 dependence.",{"@graph":69,"@context":123},[70,84,106],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":35,"@type":76,"position":81},"https://docshare.wps.com/document/healthcare/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/amitriptyline-inhibits-eag1-channels-by-binding-to-their-pas-domains-and-exerts-eag1-dependent-anti-tumorigenic-effects/352041/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/amitriptyline-inhibits-eag1-channels-by-binding-to-their-pas-domains-and-exerts-eag1-dependent-anti-tumorigenic-effects/352041.png","ImageObject",300,407,{"name":92,"@type":93},"kopisore","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-28","2026-09-22",true,{"@type":102,"interactionType":103,"userInteractionCount":105},"InteractionCounter",{"@type":104},"ViewAction",11,{"@type":107,"mainEntity":108},"FAQPage",[109,115,119],{"name":110,"@type":111,"acceptedAnswer":112},"How does amitriptyline inhibit EAG1 channels in cancer cells?","Question",{"text":113,"@type":114},"Amitriptyline binds to the PAS domains of EAG1 channels, suppressing their activity. This leads to EAG1-dependent anti-tumorigenic effects.","Answer",{"name":116,"@type":111,"acceptedAnswer":117},"Why is the effect of amitriptyline stronger in some cancer cells than others?",{"text":118,"@type":114},"The inhibitory effect is stronger in cells with high EAG1 expression (such as MDA-MB-231 and SH-SY5Y). Cells with lower EAG1 levels (such as A375) show smaller or no effects on growth and migration.",{"name":120,"@type":111,"acceptedAnswer":121},"What evidence shows that amitriptyline’s anti-cancer effects are dependent on EAG1?",{"text":122,"@type":114},"EAG1 knock-in increases drug-mediated inhibition of cell growth, while EAG1 knock-out reduces or removes the drug’s effects, including migration in MDA-MB-231 cells. Xenograft results similarly depend on EAG1 expression.","https://schema.org",{"og:url":83,"og:type":125,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":127,"canonical":83},"index,follow",{"doc_id":129,"site_id":62},352041,1790481907,{"code":4,"msg":5,"data":132},{"doc_id":129,"user_id":133,"nickname":92,"user_avatar":134,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":135,"file_id":136,"file_url":137,"file_type":138,"file_size":139,"view_count":105,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":140,"language":141,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":142,"faqs":143,"seo_title":144,"seo_description":67,"update_tm":145,"read_time":146},962090880963,"https://ap-avatar.wpscdn.com/davatar_6f874abed73319feea01a86fa6f0fab8","Cancer Gene [Therapy](Therapy www.nature.com/cgt)[ www.nature.com/cgt](Therapy www.nature.com/cgt)  \nARTICLE OPEN   \nAmitriptyline inhibits EAG1 channels by binding to their PAS domains and exerts EAG1-dependent anti-tumorigenic effects  \nJoos Berghausen 1, Clementine A. D. Thomas1, Ze-Jun Wang 1, Kyle Kihn1,2, Eric Glasgow 3 and Tinatin I. Brelidze 1 ✉  \n© The Author(s) 2026  \n|  |  |  |\n| --- | --- | --- |\n|  | Ether-a-go-go 1 (EAG1) potassium channels are overexpressed in the majority of cancers, and inhibition of their activity decreases cancer growth and migration. Here, we show that amitriptyline (AmiT), an antidepressant that is also used for pain management in cancer patients, inhibits EAG1 by binding to their PAS domains and exerts EAG1-dependent anti-tumorigenic effects. AmiT inhibited the growth of MDA-MB-231 and SH-SY5Y cells expressing EAG1 at high levels, while having a smaller effect on the growth of A375 cells expressing EAG1 at lower levels. Knocking in EAG1 in HEK293 cells increased the inhibition of cell growth by AmiT, while knocking out EAG1 in MDA-MB-231 cells decreased the inhibition of cell growth by the drug. AmiT also inhibited cell migration in MDA-MB-231 and SH-SY5Y cells, while having no effect in A375 cells. Knocking out EAG1 in MDA-MB-231 cells completely removed the effect of AmiT on cell migration. Similar to the in vitro results, AmiT inhibited the growth of MDA-MB-231 and SH-SY5Y zebrafish xenografts, while having no effect on A375 xenografts. Taken together, these results indicate that EAG1 channels are a functional target of AmiT and suggest a potential repurposing of this FDA-approved drug as an anti-cancer agent for |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n| tumors with high EAG1 expression. |  |  |\n|  | Cancer Gene Therapy (2026) 33:861–874; [https://doi.org/10.1038/s41417-026-01029-4](https://doi.org/10.1038/s41417-026-01029-4) |  |\n|  |  |  |\n\nINTRODUCTION  \nThe ether-à-go-go (EAG) 1 channel, also called Kv10.1, is a voltagedependent potassium channel, encoded by the KCNH1 gene [1] . It is part of the KCNH voltage-gated potassium channel family that additionally includes EAG-related (ERG) channels, and EAG-like K+(ELK) channels [1] . EAG1 channels are tetramers, with each subunit comprised of six transmembrane segments (S1-S6) . The S1-S4 segments form the voltage-sensing (VS) domain, and the S5 and S6 segments from all four subunits form the centrally located potassium channel pore. Intracellularly, the EAG1 channel possesses a Per-ARNT-Sim (PAS) domain at the N-terminus and a cyclic nucleotide-binding homology domain (CNBHD) at the C-terminus connected to the S6 segment via the C-linker [2, 3] .  \nEAG1 channels are almost exclusively expressed in the central nervous system (CNS) [4] . Their main function has been linked to the regulation of neural excitability by governing presynaptic Ca2+ influx and neurotransmitter release during high-frequency firing [5] . While EAG1 channels are scarcely expressed in the periphery, this changes drastically in cancer, with over 70% of cancers found to be overexpressing EAG1 channels [6–10] . Moreover, transfection of non-cancerous Chinese hamster ovary (CHO) and NIH3T3 mouse fibroblast cells with EAG1 channels induced a malignant phenotype [11] . Importantly, silencing of EAG1 channel expression decreases cancerous properties [12] . Despite their antitumorigenic potential, there are no FDA-approved EAG1 channel inhibitors.  \nThe cellular pathways affected by EAG1 channels in cancer are not fully understood and involve multiple mechanisms [13] . In  \nhepatocarcinoma cells, EAG1 has been shown to affect cell proliferation by inhibiting the degradation of SKP2, a protein involved in the degradation of cell-dependent kinase (CDK) inhibitors and ubiquitination [14, 15] . EAG1 channels are also proposed to regulate cancer progression through vascular endothelial growth factor (VEGF), an importan","cbCaimXDSXRMNtWg","https://ap.wps.com/l/cbCaimXDSXRMNtWg","pdf",5961004,14,"English","# Introduction\n## EAG1 channel structure and cancer relevance\n## Rationale for targeting EAG1\n## Prior findings on PAS-domain binding by tricyclic drugs\n# Results\n## Amitriptyline inhibits EAG1 currents via PAS-domain binding\n## Cell growth and migration across EAG1 expression levels\n## Genetic dependency experiments\n## Effects in xenograft models","[{\"question\":\"How does amitriptyline inhibit EAG1 channels in cancer cells?\",\"answer\":\"Amitriptyline binds to the PAS domains of EAG1 channels, suppressing their activity. This leads to EAG1-dependent anti-tumorigenic effects.\"},{\"question\":\"Why is the effect of amitriptyline stronger in some cancer cells than others?\",\"answer\":\"The inhibitory effect is stronger in cells with high EAG1 expression (such as MDA-MB-231 and SH-SY5Y). Cells with lower EAG1 levels (such as A375) show smaller or no effects on growth and migration.\"},{\"question\":\"What evidence shows that amitriptyline’s anti-cancer effects are dependent on EAG1?\",\"answer\":\"EAG1 knock-in increases drug-mediated inhibition of cell growth, while EAG1 knock-out reduces or removes the drug’s effects, including migration in MDA-MB-231 cells. Xenograft results similarly depend on EAG1 expression.\"}]","Amitriptyline inhibits EAG1 channels by binding to their PAS domains and exerts EAG1-dependent anti-tumorigenic effects | PDF",1790097334,35]