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MILIP also interfaces with eEF1a1 via an RNA-RNA duplex involving tRNALeu and tRNASer, and disrupting MILIP-tRNA or MILIP-eEF1a1 interactions reduces protein synthesis and viability. Targeting MILIP inhibits TNBC growth and synergizes with omacetaxine mepesuccinate in vivo, highlighting MILIP as an RNA translation elongation factor and a therapeutic target for TNBC.",{"@graph":14,"@context":73},[15,34,56],{"@type":16,"itemListElement":17},"BreadcrumbList",[18,23,27,31],{"item":19,"name":20,"@type":21,"position":22},"https://docshare.wps.com","Home","ListItem",1,{"item":24,"name":25,"@type":21,"position":26},"https://docshare.wps.com/document/","Document",2,{"item":28,"name":29,"@type":21,"position":30},"https://docshare.wps.com/document/healthcare/","Healthcare",3,{"item":32,"name":10,"@type":21,"position":33},"https://docshare.wps.com/document/milip-binding-to-trnas-promotes-protein-synthesis-to-drive-triple-negative-breast-cancer-abstract/339283/",4,{"url":32,"name":10,"@type":35,"image":36,"author":41,"headline":10,"publisher":44,"fileFormat":47,"inLanguage":8,"description":12,"dateModified":48,"datePublished":49,"encodingFormat":47,"isAccessibleForFree":50,"interactionStatistic":51},"DigitalDocument",{"url":37,"@type":38,"width":39,"height":40},"https://docshare.wps.com/thumbnails/milip-binding-to-trnas-promotes-protein-synthesis-to-drive-triple-negative-breast-cancer-abstract/339283.png","ImageObject",300,407,{"name":42,"@type":43},"Emma 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diminishes protein synthesis and reduces TNBC cell viability and growth.","https://schema.org",{"og:url":32,"og:type":75,"og:title":10,"og:site_name":45,"og:description":12},"article",{"robots":77,"canonical":32},"index,follow",{"doc_id":79,"site_id":7},339283,1790367913,{"code":4,"msg":82,"data":83},"success",[84,88,92,96,101,106,110,114,119,122,126],{"id":22,"doc_module":4,"doc_module_name":25,"category_name":85,"show_sort_weight":86,"slug":87},"Story & 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Feng3, Qin Zhu1, Ruo Qi Li1, Qian Qian Yan2, Liu Teng2, Yi Meng Yue2, Man Man Han2, Kaihong Ye2, Sheng Nan Zhang2, Teng Fei Qi2, Cai Xia Tang2, Xiao Hong Zhao4, Yuan Yuan Zhang4, Liang Xu4, Ran Xu4, Jun Xing1, Mark Baker4, Tao Liu5, Rick F. Thorne4, Lei Jin3, Thomas Preiss6,7, Xu Dong Zhang2,4, Shundong Cang8, and Jin Nan Gao1  \nABSTRACT  \n\n| ◥\u003Cbr>Patients with triple-negative breast cancer (TNBC) have a poor prognosis due to the lack of effective molecular targets for therapeutic intervention. Here we found that the long noncoding RNA (lncRNA) MILIP supports TNBC cell survival, proliferation, and tumorigenicity by complexing with transfer RNAs (tRNA) to promote protein production, thus representing a potential therapeutic target in TNBC. MILIP was expressed at high levels in TNBC cells that commonly harbor loss-of-function mutations of the tumor suppressor p53, and MILIP silencing suppressed TNBC cell viability and xenograft growth, indicating that MILIP functions distinctively in TNBC beyond its established role in repressing p53 in other types of cancers. Mechanistic investigations revealed that MILIP interacted with eukaryotic translation elongation factor 1 alpha 1 (eEF1a 1) and formed an RNA-RNA duplex with the type II tRNAs tRNALeu and tRNASer through | their variable loops, which facilitated the binding of eEF1a 1 to these tRNAs. Disrupting the interaction between MILIP andeEF1a1 or tRNAs diminished protein synthesis and cell viability. Targeting MILIP inhibited TNBC growth and cooperated with the clinically available protein synthesis inhibitor omacetaxinemepesuccinate in vivo. Collectively, these results identify MILIP asan RNA translation elongation factor that promotes protein production in TNBC cells and reveal the therapeutic potential of targeting MILIP, alone and in combination with other types of protein synthesis inhibitors, for TNBC treatment.\u003Cbr>Significance: LncRNA MILIP plays a key role in supporting protein production in TNBC by forming complexes with tRNAsandeEF1a1, which confers sensitivity to combined MILIP targeting and protein synthesis inhibitors.\u003Cbr>(TNBC), one of the most aggressive types of breast cancer, is challenging, with chemotherapy still remaining the mainstay of treatment options (1) . Nevertheless, there are enormous strides underway to treat TNBC more effectively (1) . For example, the FDA has approved the anti-programmed death-ligand 1 (PD-L1) mAb atezolizumab, in combination with the chemotherapy drug paclitaxel, for the treatment of unresectable locally advanced or metastatic TNBC that expresses PD-L1, whereas the PARP inhibitors olaparib and talazoparib are used for the treatment of TNBC with breast cancer susceptibility gene (BRCA) mutations (2, 3) .\u003Cbr>Cancer cells, including those ofTNBC, often boost protein biosynthesis to meet the high protein demands required for supporting their survival and rapid proliferation (4) . Consequently, targeting protein biosynthesis is emerging as a promising approach for cancer treatment (5) . Indeed, mTOR inhibitors are used clinically to target the protein synthesis pathway in various types of cancer, including everolimusin hormone receptor–positive, receptor tyrosine-protein kinaseerbB-2 (HER2)-negative breast cancer in postmenopausal patients, whereas omacetaxine mepesuccinate [INN, also known as homoharringtonine (HHT)] that blocks the initial step of translation elongation is used to treat chronic myeloid leukemia (6, 7) . Nevertheless, no protein synthesis inhibitor has yet entered clinical practice for the treatment of TNBC (8) .\u003Cbr>The role oflong noncoding RNAs(lncRNA)in cancer development, progression, and treatment resistance is increasingly appreciated (9, 10) . In particular, a number of lncRNAs have been linked to regulation of mRNA translation (11) . For instance, the lncRNA BC200 interacts with the translation initi","cbCainAEfeUJ6xgq","https://ap.wps.com/l/cbCainAEfeUJ6xgq","pdf",5990616,15,"English","# Abstract\n## Introduction\n## General Surgery Department","[{\"question\":\"What problem in triple-negative breast cancer does this study address?\",\"answer\":\"TNBC has a poor prognosis due to the lack of effective molecular targets for therapeutic intervention.\"},{\"question\":\"How does the long noncoding RNA MILIP contribute to TNBC?\",\"answer\":\"MILIP promotes TNBC cell survival, proliferation, and tumorigenicity by complexing with tRNAs to enhance protein production.\"},{\"question\":\"What happens when the MILIP interaction with tRNAs or eEF1a1 is disrupted?\",\"answer\":\"Disrupting MILIP-tRNA or MILIP-eEF1a1 interactions diminishes protein synthesis and reduces TNBC cell viability and growth.\"}]","MILIP Binding to tRNAs Promotes Protein Synthesis to Drive Triple-Negative Breast Cancer - Abstract | PDF",1790029205,38]