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This work investigates how capsaicin inhibits Hsp90, showing direct binding to the N-terminus and suppression of ATPase activity. Capsaicin selectively promotes lysosome-autophagy–dependent degradation of Hsp70 without inducing the heat shock response (HSR), and enhances 17-AAG (Tanespimycin) anti-tumor effects in cell and tumor spheroid models. Docking indicates a distinct binding mode from classical N-terminal inhibitors, supporting capsaicin as a scaffold for novel Hsp90 N-terminus inhibitors and as a potential co-therapeutic.",{"@graph":69,"@context":122},[70,84,105],{"@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/capsaicin-binds-the-n-terminus-of-hsp90-induces-lysosomal-degradation-of-hsp70-and-enhances-the-anti-tumor-effects-of-17-aag-tanespimycin/380328/",{"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/capsaicin-binds-the-n-terminus-of-hsp90-induces-lysosomal-degradation-of-hsp70-and-enhances-the-anti-tumor-effects-of-17-aag-tanespimycin/380328.png","ImageObject",300,407,{"name":92,"@type":93},"Fahsai","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-25","2026-09-24",true,{"@type":102,"interactionType":103,"userInteractionCount":24},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"How does capsaicin inhibit Hsp90 according to the study?","Question",{"text":112,"@type":113},"Capsaicin binds to the N-terminus of Hsp90 and inhibits its ATPase activity.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"Does capsaicin induce the cellular heat shock response (HSR)?",{"text":117,"@type":113},"No. Instead, capsaicin promotes degradation of Hsp70 through the lysosome-autophagy pathway and does not induce degradation of constitutively expressed Hsc70.",{"name":119,"@type":110,"acceptedAnswer":120},"What is the effect of combining capsaicin with 17-AAG (Tanespimycin)?",{"text":121,"@type":113},"Combined treatments improve the anti-tumor efficacy of 17-AAG in cell culture and tridimensional tumor spheroid growth assays using breast and prostate cancer models.","https://schema.org",{"og:url":83,"og:type":124,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":126,"canonical":83},"index,follow",{"doc_id":128,"site_id":62},380328,1790870480,{"code":4,"msg":5,"data":131},{"doc_id":128,"user_id":132,"nickname":92,"user_avatar":133,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":24,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":139,"language":140,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":141,"faqs":142,"seo_title":143,"seo_description":67,"update_tm":144,"read_time":145},549768702563,"https://ap-avatar.wpscdn.com/avatar/8000c4aa63b76e948b?x-image-process=image/resize,m_fixed,w_180,h_180&k=1786536092046926083","[www. nature.com/scientificreports](www. nature.com/scientificreports)  \nOPEN  \nCapsaicin binds the N‑terminus of Hsp90, induces lysosomal degradation of Hsp70, and enhances the anti‑tumor effects of 17‑AAG (Tanespimycin)  \nChaitanya A. Patwardhan1, Vamsi Krishna Kommalapati1, Taoufik Llbiyi1, Digvijay Singh1, Eyad Alfa1, Anatolij Horuzsko1, Hasan Korkaya1, Siva Panda2, Christopher A. Reilly 3, Vladimir Popik4 & Ahmed Chadli1*  \nHeat shock protein 90 (Hsp90) and its co‑chaperones promote cancer, and targeting Hsp90 holds promise for cancer treatment. Most of the efforts to harness this potential have focused on targeting the Hsp90 N‑terminus ATP binding site. Although newer‑generation inhibitors have shown improved efficacy in aggressive cancers, induction of the cellular heat shock response (HSR) by these inhibitors is thought to limit their clinical efficacy. Therefore, Hsp90 inhibitors with novel mechanisms of action and that do not trigger the HSR would be advantageous. Here, we investigated the mechanism by which capsaicin inhibits Hsp90. Through mutagenesis, chemical modifications, and proteomic studies, we show that capsaicin binds to the N‑terminus of Hsp90 and inhibits its ATPase activity. Consequently, capsaicin and its analogs inhibit Hsp90 ATPase‑dependent progesterone receptor reconstitution in vitro. Capsaicin did not induce the HSR, instead, it promoted the degradation of Hsp70 through the lysosome‑autophagy pathway. Remarkably, capsaicin did not induce degradation of the constitutively expressed cognate Hsc70, indicating selectivity for Hsp70 . Combined treatments of capsaicin and the Hsp90 inhibitor 17‑AAG improved the anti‑tumor efficacy of 17‑AAG in cell culture and tridimensional tumor spheroid growth assays using breast and prostate cancer models. Consistent with this, in silico docking studies revealed that capsaicin binding to the ATP binding site of Hsp90 was distinct from classical N‑terminus Hsp90 inhibitors, indicating a novel mechanism of action. Collectively, these findings support the use of capsaicin as a chemical scaffold to develop novel Hsp90 N‑terminus inhibitors as well as its ability to be a potential cancer co‑therapeutic.  \nThe chaperome is composed of chaperone and co-chaperone proteins that safeguard cellular proteostasis and thus plays a key role in determining cancer phenotypes. Cancer cells over-express molecular chaperones and co-chaperones, including Hsp90, Hsp70, Hsp90/Hsp70 organizing protein (HOP), Hsp40, p23, and CDC37, that are necessary to fold mutant proteins and other highly expressed proteins1–3. Early studies have shown that heat shock protein 90 (Hsp90) is enriched in dynamic complexes with co-chaperones in tumor tissues compared to normal tissue4,5. Consistent with this, recent findings revealed the existence of a more complex molecular rewiring of the Hsp70 and Hsp90 chaperone networks to form a highly integrated complex, referred to as the epichaperome, in cancer cells. This pathologic protein–protein interaction network has been shown to promote cancer cell survival and aggressiveness of certain tumors6. The epichaperome may also be amenable to drug targeting7.  \nHsp90 has been recognized as a therapeutic target for cancer therapy for decades1. Extensive efforts have led to the discovery of multiple Hsp90 inhibitors. Compounds of a diverse chemical nature, including geldanamycin derivatives, resorcinol group-containing compounds, purine and purine-like analogs, and others, have  \n1Georgia Cancer Center at Augusta University (Formerly Medical College of Georgia), 1410 Laney Walker Blvd, CN-3313, Augusta, GA 30912, USA. 2Department of Chemistry and Biochemistry, Augusta University, Augusta, GA 30912, USA. 3Department of Pharmacology and Toxicology, Center for Human Toxicology, College of Pharmacy, University of Utah, Salt Lake City, UT 84112, USA. 4Department of Chemistry, University of Georgia, Athens, GA 30602, USA.* email: [achadli@augusta.edu](achadli@augusta.edu) ","cbCaibUqT8XbPeZJ","https://ap.wps.com/l/cbCaibUqT8XbPeZJ","pdf",6367882,15,"English","# Capsaicin inhibition of Hsp90\n## Mechanism: N-terminus binding and ATPase suppression\n## Cellular effects: no HSR, lysosome-autophagy degradation of Hsp70\n## Combination therapy: enhanced 17-AAG anti-tumor efficacy\n## Distinct binding mode: docking versus classical inhibitors","[{\"question\":\"How does capsaicin inhibit Hsp90 according to the study?\",\"answer\":\"Capsaicin binds to the N-terminus of Hsp90 and inhibits its ATPase activity.\"},{\"question\":\"Does capsaicin induce the cellular heat shock response (HSR)?\",\"answer\":\"No. Instead, capsaicin promotes degradation of Hsp70 through the lysosome-autophagy pathway and does not induce degradation of constitutively expressed Hsc70.\"},{\"question\":\"What is the effect of combining capsaicin with 17-AAG (Tanespimycin)?\",\"answer\":\"Combined treatments improve the anti-tumor efficacy of 17-AAG in cell culture and tridimensional tumor spheroid growth assays using breast and prostate cancer models.\"}]","Capsaicin binds the N-terminus of Hsp90, induces lysosomal degradation of Hsp70, and enhances the anti-tumor effects of 17-AAG (Tanespimycin) | PDF",1790239750,38]