[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"detail-sidebar-cat-0-en-105":3,"doc-seo-369588-105":59,"doc-detail-369588-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","bypassing-the-guardian-regulated-cell-death-pathways-in-p53-mutant-cancers","Bypassing the Guardian - Regulated Cell Death Pathways in p53-Mutant Cancers","","Approximately half of all cancers involve tumor suppressor p53 mutations, making p53-mutant cancer therapy difficult due to how these mutations remodel interrelated signaling networks that drive metastasis and chemoresistance. p53 mutations promote tumor survival by disrupting cellular homeostasis and blocking regulated cell death (RCD). RCD activation is linked to effective cancer treatment, and p53-mutant cancers may be especially vulnerable to specific RCD routes. This review examines four targetable RCD pathways and summarizes activation mechanisms, p53 impacts, and current drug strategies.",{"@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/bypassing-the-guardian-regulated-cell-death-pathways-in-p53-mutant-cancers/369588/",{"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/bypassing-the-guardian-regulated-cell-death-pathways-in-p53-mutant-cancers/369588.png","ImageObject",300,407,{"name":92,"@type":93},"นรินทร์","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-28","2026-09-23",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},"Why are p53-mutant cancers difficult to treat?","Question",{"text":113,"@type":114},"p53 mutations rewire complex signaling networks that support metastasis and chemoresistance, and they interfere with regulated cell death pathways that normally remove dysregulated cells.","Answer",{"name":116,"@type":111,"acceptedAnswer":117},"What does the review focus on regarding regulated cell death?",{"text":118,"@type":114},"It discusses four RCD pathways targeted by emerging cancer therapeutics: E2F1-dependent apoptosis, necroptosis, mitochondrial permeability transition-driven necrosis, and ferroptosis.",{"name":120,"@type":111,"acceptedAnswer":121},"How does p53 promote intrinsic apoptosis under cellular stress?",{"text":122,"@type":114},"Cell-intrinsic stress inhibits MDM2, allowing p53 to accumulate and activate transcription of proapoptotic factors, leading to mitochondrial cytochrome c release and caspase activation that drives cell death.","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},369588,1790219455,{"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},2336475104957,"https://ap-avatar.wpscdn.com/avatar/22000c4c6bd8a5076e1?x-image-process=image/resize,m_fixed,w_180,h_180&k=1787554080175789136","Chung and Knutson  \nCellular & Molecular Biology Letters (2025) 30:68 [https://doi.org/10.1186/s11658-025-00751-5](https://doi.org/10.1186/s11658-025-00751-5)  \nCellular & Molecular Biology Letters  \nREVIEW Open Access  \nBypassing the guardian: regulated cell death   pathways in p53-mutant cancers  \nJonathan Y. Chung 1* and Bruce A. Knutson 1*  \n*Correspondence: [chungjo@upstate.edu](chungjo@upstate.edu); [knutsonb@upstate.edu](knutsonb@upstate.edu)  \n1 Department of Biochemistry and Molecular Biology, State University of New York Upstate Medical University, Syracuse, NY 13210, USA  \nAbstract  \nApproximately half of all cancers bear mutations in the tumor suppressor p53 . Despite decades of research studying p53 function, treatment of p53-mutant cancers remains challenging owing to the effects of p53 mutations on many complex and interrelated signaling networks that promote tumor metastasis and chemoresistance. Mutations in p53 promote tumor survival by dysregulating cellular homeostasis and preventing activation of regulated cell death (RCD) pathways, which normally promote organismal health by eliminating dysregulated cells. Activation of RCD is a hallmark of effective cancer therapies, and p53-mutant cancers may be particularly susceptible to activation of certain RCD pathways. In this review, we discuss four RCD pathways that are the targets of emerging cancer therapeutics to treat p53-mutant cancers. These RCD pathways include E2F1-dependent apoptosis, necroptosis, mitochondrial permeability transition-driven necrosis, and ferroptosis. We discuss mechanisms of RCD activation, effects of p53 mutation on RCD activation, and current pharmaceutical strategies for RCD activation in p53-mutant cancers.  \nKeywords: P53, Cancer, Metastasis, Apoptosis, Necroptosis, Ferroptosis, Reactive oxygen species  \n© The Author(s) 2025. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit [http://](http://)[ ](http://)[creativecommons.org/licenses/by/4.0/](creativecommons.org/licenses/by/4.0/.)[.](creativecommons.org/licenses/by/4.0/.)  \nChung and Knutson Cellular & Molecular Biology Letters (2025) 30:68 Page 2 of 34  \nGraphical Abstract  \nIntroduction  \nBiomedical scientists have extensively studied the p53 transcription factor since David Lane and Lionel Crawford discovered p53 in 1979 [1] . After being misidentified asan oncoprotein, p53’s important function in tumor suppression was only appreciated after establishment of the murine wild-type p53 protein sequence [2] . A total of 10 years after the initial discovery of p53, Bert Vogelstein and colleagues demonstrated that p53 mutation and deletion occur at an extremely high frequency in colorectal carcinomas, providing compelling evidence that p53 functions as a tumor suppressor [3] . Generations of researchers have since shown that p53, known as the “guardian of the genome,” mediates several critical functions in tumor suppression including DNA  \ndamage repair, metastasis prevention, and induction of growth arrest and apoptosis.  \np53’s role in apoptosis has garnered particular interest with respect to cancer therapy. Apoptosis and other regulated cell death (RCD) pathways maintain organismal homeostasis by removing unneeded or unwanted cells [4] . I","cbCaiqSreMVCHv1x","https://ap.wps.com/l/cbCaiqSreMVCHv1x","pdf",3643912,34,"English","# Introduction\n## p53 and regulated cell death (RCD)\n## p53-dependent apoptosis and cancer therapy","[{\"question\":\"Why are p53-mutant cancers difficult to treat?\",\"answer\":\"p53 mutations rewire complex signaling networks that support metastasis and chemoresistance, and they interfere with regulated cell death pathways that normally remove dysregulated cells.\"},{\"question\":\"What does the review focus on regarding regulated cell death?\",\"answer\":\"It discusses four RCD pathways targeted by emerging cancer therapeutics: E2F1-dependent apoptosis, necroptosis, mitochondrial permeability transition-driven necrosis, and ferroptosis.\"},{\"question\":\"How does p53 promote intrinsic apoptosis under cellular stress?\",\"answer\":\"Cell-intrinsic stress inhibits MDM2, allowing p53 to accumulate and activate transcription of proapoptotic factors, leading to mitochondrial cytochrome c release and caspase activation that drives cell death.\"}]","Bypassing the Guardian - Regulated Cell Death Pathways in p53-Mutant Cancers | PDF",1790183573,86]