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Prior work showed that inhibiting heat shock protein 27 (HSP27) or fatty acid oxidation (FAO) sensitizes cisplatin-resistant ovarian cancer cell lines, and dual inhibition can trigger marked in vitro cell death. This study clarifies the underlying mechanisms and tests whether combined inhibition augments cisplatin therapy in vivo. HSP27 knockdown increased cisplatin-driven ROS while reducing GSH and G6PD, and ROS scavenging with NAC reduced HSP27/FAO induction and apoptosis/ferroptosis markers. Finally, ivermectin and perhexiline enhanced cisplatin cytotoxicity in A2780CIS xenografts. Results suggest HSP27 and FAO upregulate to deplete cisplatin-induced ROS and thereby protect resistant cells.",{"@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/targeting-heat-shock-protein-27-and-fatty-acid-oxidation-augments-cisplatin-treatment-in-cisplatin-resistant-ovarian-cancer-cell-lines/383973/",{"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/targeting-heat-shock-protein-27-and-fatty-acid-oxidation-augments-cisplatin-treatment-in-cisplatin-resistant-ovarian-cancer-cell-lines/383973.png","ImageObject",300,407,{"name":92,"@type":93},"Melati","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-11-04","2026-09-24",true,{"@type":102,"interactionType":103,"userInteractionCount":105},"InteractionCounter",{"@type":104},"ViewAction",15,{"@type":107,"mainEntity":108},"FAQPage",[109,115,119],{"name":110,"@type":111,"acceptedAnswer":112},"Why is cisplatin ineffective for many ovarian cancer patients over time?","Question",{"text":113,"@type":114},"Most patients initially respond to cisplatin, but a large fraction later develop recurrent ovarian cancer that no longer responds to continued cisplatin treatment.","Answer",{"name":116,"@type":111,"acceptedAnswer":117},"What is the role of HSP27 and FAO in cisplatin-resistant ovarian cancer cells?",{"text":118,"@type":114},"Cisplatin-resistant cells upregulate HSP27 and fatty acid oxidation to counteract cisplatin-induced reactive oxygen species, thereby reducing cisplatin cytotoxicity.",{"name":120,"@type":111,"acceptedAnswer":121},"How does inhibiting HSP27 and FAO affect cisplatin treatment in vivo?",{"text":122,"@type":114},"Using ivermectin and perhexiline to inhibit HSP27 and FAO enhanced the cytotoxic effect of cisplatin in A2780CIS xenograft tumors, supporting improved therapeutic efficacy.","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},383973,1790486168,{"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":36},962085570644,"https://ap-avatar.wpscdn.com/davatar_994ba38a5ba835b3df7d355c54d3ed8d","Article  \nTargeting Heat Shock Protein 27 and Fatty Acid Oxidation Augments Cisplatin Treatment in Cisplatin-Resistant Ovarian Cancer Cell Lines  \nJames Patrick Heiserman, Zenab Minhas, Elahe Nikpayam and Dong-Joo Cheon *  \nCitation: Heiserman, J.P.; Minhas, Z.; Nikpayam, E.; Cheon, D.-J. Targeting Heat Shock Protein 27 and Fatty Acid Oxidation Augments Cisplatin Treatment in Cisplatin-Resistant Ovarian Cancer Cell Lines. Int. J. Mol. Sci. 2023, 24, 12638. [https://doi.org/](https://doi.org/)[ ](https://doi.org/)[10.3390/ijms241612638](10.3390/ijms241612638)  \nAcademic Editors: Nicola Margiotta, James D. Hoeschele and  \nValentina Gandin  \nReceived: 27 June 2023  \nRevised: 4 August 2023  \nAccepted: 7 August 2023  \nPublished: 10 August 2023  \nCopyright: © 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ([https://](https://)[ ](https://)[creativecommons.org/licenses/by/](creativecommons.org/licenses/by/)[ ](creativecommons.org/licenses/by/)[4.0/](4.0/)) .  \nDepartment of Regenerative and Cancer Cell Biology, Albany Medical College, Albany, NY 12208, USA;  \n[jimheiserman@gmail.com](jimheiserman@gmail.com) (J.P.H.); [nikpaye@amc.edu](nikpaye@amc.edu) (E.N.)  \n* Correspondence: [cheond@amc.edu](cheond@amc.edu)  \nAbstract: Most ovarian cancer patients develop recurrent cancers which are often resistant to commonly employed chemotherapy agents, such as cisplatin. We have previously shown that the inhibition of heat shock protein 27 (HSP27) or fatty acid oxidation (FAO) sensitizes cisplatin-resistant ovarian cancer cell lines to cisplatin and dual inhibition of both HSP27 and FAO induces substantial cell death in vitro. However, it is unclear how HSP27 and FAO promote cisplatin resistance, and if dual inhibition of both HSP27 and FAO would augment cisplatin treatment in vivo. Here we showed that HSP27 knockdown in two cisplatin-resistant ovarian cancer cell lines (A2780CIS and PEO4) resulted in more ROS production upon cisplatin treatment. HSP27-knockdown cancer cells exhibited decreased levels of reduced glutathione (GSH) and glucose6phosphate dehydrogenase (G6PD), a crucial pentose phosphate pathway enzyme. ROS depletion with the compound N-acetyl cysteine (NAC) attenuated cisplatin-induced upregulation of HSP27, FAO, and markers of apoptosis and ferroptosis in cisplatin-resistant ovarian cancer cell lines. Finally, inhibition of HSP27 and FAO with ivermectin and perhexiline enhanced the cytotoxic effect of cisplatin in A2780CIS xenograft tumorsin vivo. Our results suggest that two different cisplatin-resistant ovarian cancer cell lines upregulate HSP27 and FAO to deplete cisplatin-induced ROS to attenuate cisplatin's cytotoxic effect.  \nKeywords: ovarian cancer; cisplatin resistance; HSP27; FAO; ROS  \n1. Introduction  \nOvarian cancer is the fifth leading cause of cancer mortalities for women in the United States [1] . Cisplatin is an FDA-approved platinum-based chemotherapy drug for the treatment of ovarian cancer [2] . Although 85% of ovarian cancer patients initially respond to cisplatin treatment, unfortunately 75% of patients will subsequently develop recurrent ovarian cancer, which likely will no longer respond to subsequential cisplatin treatment [3] . Considering this, it is important to understand the mechanisms of cisplatin resistance to develop a novel therapy to overcome cisplatin resistance.  \nPreviously, our group reported that COL11A1, a gene encoding collagen 􀀋1(XI), is highly upregulated in cisplatin-resistant ovarian cancers [4,5] . We further showed that collagen 􀀋1(XI) promotes cisplatin resistance by upregulating heat shock protein 27 (HSP27) or fatty acid oxidation (FAO) in ovarian cancer cells [4,5] . Interestingly, the genetic and pharmaceutical inhibition of HSP27 upregulated carnitine palmitoyltransferase I alpha (CPT1A), the rate-limiting enzyme of FAO, to sustain ovar","cbCaibyP9TQj8A18","https://ap.wps.com/l/cbCaibyP9TQj8A18","pdf",3881531,16,"English","# Introduction\n## Ovarian cancer burden and cisplatin resistance\n## Prior findings on HSP27 and FAO in resistance","[{\"question\":\"Why is cisplatin ineffective for many ovarian cancer patients over time?\",\"answer\":\"Most patients initially respond to cisplatin, but a large fraction later develop recurrent ovarian cancer that no longer responds to continued cisplatin treatment.\"},{\"question\":\"What is the role of HSP27 and FAO in cisplatin-resistant ovarian cancer cells?\",\"answer\":\"Cisplatin-resistant cells upregulate HSP27 and fatty acid oxidation to counteract cisplatin-induced reactive oxygen species, thereby reducing cisplatin cytotoxicity.\"},{\"question\":\"How does inhibiting HSP27 and FAO affect cisplatin treatment in vivo?\",\"answer\":\"Using ivermectin and perhexiline to inhibit HSP27 and FAO enhanced the cytotoxic effect of cisplatin in A2780CIS xenograft tumors, supporting improved therapeutic efficacy.\"}]","Targeting Heat Shock Protein 27 and Fatty Acid Oxidation Augments Cisplatin Treatment in Cisplatin-Resistant Ovarian Cancer Cell Lines | PDF",1790260519]