Cancer lettersPub Date : 2025-03-26DOI: 10.1016/j.canlet.2025.217660
Yafei Wang , Ying Yu , Jiahua Yu , Cheng Wang , Yunkun Wang , Runxi Fu , Chenran Zhang
{"title":"The intersections between neuroscience and medulloblastoma","authors":"Yafei Wang , Ying Yu , Jiahua Yu , Cheng Wang , Yunkun Wang , Runxi Fu , Chenran Zhang","doi":"10.1016/j.canlet.2025.217660","DOIUrl":"10.1016/j.canlet.2025.217660","url":null,"abstract":"<div><div>Medulloblastoma (MB) represents the most common malignant central nervous system tumor in childhood. The nervous system plays a critical role in the progression of MB, with interactions between the nervous system and cancer significantly influencing oncogenesis, tumor growth, invasion, stemness, and metabolism. These interactions also regulate angiogenesis, metastatic dissemination, the tumor immune microenvironment, and drug resistance. Investigating the nervous system-MB axis holds promise for identifying diagnostic markers, prognostic biomarkers, and therapeutic targets. It also provides insights into the molecular mechanisms underlying MB and informs the development of novel therapeutic strategies.</div><div>This review summarizes the latest advancements in understanding the interplay between the nervous system and MB, including the role of glial cells in MB and the potential of drug repurposing targeting nervous system components for MB treatment. These findings underscore promising diagnostic and therapeutic opportunities for MB management. Additionally, we outline future research directions in neurosciences that may pave the way for innovative therapeutic approaches and deepen our understanding of this complex disease.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"620 ","pages":"Article 217660"},"PeriodicalIF":9.1,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143742529","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cancer lettersPub Date : 2025-03-25DOI: 10.1016/j.canlet.2025.217666
Marta Maleszewska , Adrià-Jaume Roura , Michal J. Dabrowski , Michal Draminski , Bartosz Wojtas
{"title":"Decoding glioblastoma’s diversity: are neurons part of the game?","authors":"Marta Maleszewska , Adrià-Jaume Roura , Michal J. Dabrowski , Michal Draminski , Bartosz Wojtas","doi":"10.1016/j.canlet.2025.217666","DOIUrl":"10.1016/j.canlet.2025.217666","url":null,"abstract":"<div><div>Glioblastoma multiforme (GBM, WHO Grade 4) is a highly aggressive primary brain tumor with limited treatment options and a poor prognosis. A key challenge in GBM therapy lies in its pronounced heterogeneity, both within individual tumors (intratumoral) and between patients (intertumoral). Historically, neurons have been underexplored in GBM research; however, recent studies reveal that GBM development is closely linked to neural and glial progenitors, often mimicking neurodevelopmental processes in a dysregulated manner. Beyond damaging neuronal tissue, GBM actively engages with neurons to promote pro-tumorigenic signaling, including neuronal hyperexcitability and seizures.</div><div>Single-cell RNA sequencing (scRNA-seq) has revolutionized our understanding of the tumor microenvironment (TME), uncovering the critical roles of immune cells, endothelial cells, and astrocytes in tumor progression. However, technical limitations of scRNA-seq hinder its ability to capture the transcriptomes of neurons, necessitating the use of single-nucleus RNA sequencing (snRNA-seq) to study these interactions at single-cell resolution. This work collects the emerging insights of glioblastoma-neuron interactions, focusing on how GBM exploits neurodevelopmental pathways and reshapes neuronal networks. Moreover, we perform bioinformatic analysis of publicly available snRNA-seq datasets to propose putative cell-cell interactions driving glioma-neuronal dynamics. This study delineates key signaling pathways and underscores the need for further investigation to evaluate their potential as therapeutic targets.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"620 ","pages":"Article 217666"},"PeriodicalIF":9.1,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143728715","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cancer lettersPub Date : 2025-03-25DOI: 10.1016/j.canlet.2025.217645
ZhiZhen Li , YuanYuan Chen , XuAn Wang , HongChen Zhang , Yijian Zhang , YaoHui Gao , Mingzhe Weng , Lei Wang , HaiBin Liang , MaoLan Li , Fei Zhang , Shuai Zhao , Shibo Liu , Yang Cao , Yijun Shu , Runfa Bao , Jian Zhou , Xiyong Liu , Yun Yan , Lei Zhen , Yingbin Liu
{"title":"Corrigendum to “LASP-1 induces proliferation, metastasis and cell cycle arrest at the G2/M phase in gallbladder cancer by down-regulating S100P via the PI3K/AKT pathway” [Cancer Lett. 372 (2016) 239–250]","authors":"ZhiZhen Li , YuanYuan Chen , XuAn Wang , HongChen Zhang , Yijian Zhang , YaoHui Gao , Mingzhe Weng , Lei Wang , HaiBin Liang , MaoLan Li , Fei Zhang , Shuai Zhao , Shibo Liu , Yang Cao , Yijun Shu , Runfa Bao , Jian Zhou , Xiyong Liu , Yun Yan , Lei Zhen , Yingbin Liu","doi":"10.1016/j.canlet.2025.217645","DOIUrl":"10.1016/j.canlet.2025.217645","url":null,"abstract":"","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"619 ","pages":"Article 217645"},"PeriodicalIF":9.1,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143704394","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cancer lettersPub Date : 2025-03-25DOI: 10.1016/j.canlet.2025.217677
Rubina Kousar , Tahira Akhtar , Chin-Jung Lin , Timofey Lebedev , Yi-Chuan Li , Chih-Chao Yang , Wei-Jan Wang , Hsiao-Fan Chen , Wen-Chi Su , Pulak Kumar Biswas , Najm Us Saqib , Sefealem Assefa Belay , Tzu-Chi Chang , Da-Wei Guo , Qiangdu Li , Bbumba Patrick , Muhammad Usama , Chen-Shiou Wu , Wen-Lung Ma , Yuh-Pyng Sher , Xing-Guo Li
{"title":"Anti-SARS-CoV-2 and anticancer properties of triptolide and its derived carbonized nanomaterials","authors":"Rubina Kousar , Tahira Akhtar , Chin-Jung Lin , Timofey Lebedev , Yi-Chuan Li , Chih-Chao Yang , Wei-Jan Wang , Hsiao-Fan Chen , Wen-Chi Su , Pulak Kumar Biswas , Najm Us Saqib , Sefealem Assefa Belay , Tzu-Chi Chang , Da-Wei Guo , Qiangdu Li , Bbumba Patrick , Muhammad Usama , Chen-Shiou Wu , Wen-Lung Ma , Yuh-Pyng Sher , Xing-Guo Li","doi":"10.1016/j.canlet.2025.217677","DOIUrl":"10.1016/j.canlet.2025.217677","url":null,"abstract":"<div><div>The COVID-19 pandemic remains an ongoing global health threat, yet effective treatments are still lacking. This has led to a high demand for complementary/alternative medicine, such as Chinese herbal medicines for curbing the COVID-19 pandemic. Given the dual anticancer and antiviral activities of many herbal drugs, they may hold a multifaceted potential to tackle both cancer and SARS-CoV-2. Triptolide is the major bioactive compound isolated from Tripterygium wilfordii Hook F (TwHF), a traditional Chinese medicinal herb recognized for its beneficial pharmacological properties in many diseases, including cancer and viral infection. However, its application in the clinic has been greatly limited due to its toxicity and poor water solubility. Here, from a screen of a natural compound library of Chinese Pharmacopoeia, we identified triptolide as a top candidate to inhibit cell entry of SARS-CoV-2. We demonstrated that triptolide robustly blocked viral entry at nanomolar concentrations in cellular models, with broad range activity against emerging Omicron variants of SARS-CoV-2. Mechanistically, triptolide disrupted the interaction of SARS-CoV-2 spike protein with its receptor ACE2. Furthermore, we synthesized water-soluble, triptolide-derived carbon quantum dots. Compared to triptolide, these highly biocompatible nanomaterials exhibited prominent antiviral capabilities against Omicron variants of SARS-CoV-2 with less cytotoxicity. Finally, we showed that triptolide-derived carbonized materials excelled in their anticancer properties compared to triptolide and Minnelide, a water-soluble analog of triptolide. Together, our results provide a rationale for the potential development of triptolide-carbonized derivatives as a promising antiviral candidate for the current pandemic and future outbreaks, as well as anticancer agents.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"619 ","pages":"Article 217677"},"PeriodicalIF":9.1,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143724516","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cancer lettersPub Date : 2025-03-24DOI: 10.1016/j.canlet.2025.217659
Qiang Guo , Mei-Yu Quan , Jingyu Zheng , Chenhua Yu , Linglong Yang , Jiaqi Li , Qiongxia Weng , Qhaweni Dhlamini , Weiwei Yang , Jueting Cai , Geriletu Ao , Lifeng Chen , Jian-Min Li , Xiaodong Cheng , Xuru Jin , Yi Xu , Jin-San Zhang
{"title":"Hypoxia-induced NDRG1 C-terminal poly-phosphorylation impairs its tumor suppressor function in renal cell carcinoma","authors":"Qiang Guo , Mei-Yu Quan , Jingyu Zheng , Chenhua Yu , Linglong Yang , Jiaqi Li , Qiongxia Weng , Qhaweni Dhlamini , Weiwei Yang , Jueting Cai , Geriletu Ao , Lifeng Chen , Jian-Min Li , Xiaodong Cheng , Xuru Jin , Yi Xu , Jin-San Zhang","doi":"10.1016/j.canlet.2025.217659","DOIUrl":"10.1016/j.canlet.2025.217659","url":null,"abstract":"<div><div>Hypoxia is a critical factor driving tumor invasion and metastasis. N-myc Downstream Regulated Gene 1 (NDRG1), a known suppressor of invasion and metastasis in various cancers including clear cell renal cell carcinoma (ccRCC), remains poorly understood in the context of hypoxic regulation. Notably, the carboxy terminus (C-terminus) of NDRG1 contains multiple phosphorylation sites within a unique three-tandem-repeat sequence that responds to hypoxic conditions. However, the precise regulatory mechanisms and functional significance of phosphorylation in this region remain unexplored.</div><div>Our research uncovered that hypoxia triggers poly-phosphorylation at the C-terminus of NDRG1, thereby facilitating epithelial-mesenchymal transition (EMT) in ccRCC. NDRG1 knockdown alone was sufficient to induce EMT, augmenting the invasive and metastatic capabilities of ccRCC cells. Specifically, hypoxia-induced phosphorylation at the C-terminus (sites 328/330 and 346/356/366, phosphorylated by SGK1) of NDRG1 enhances its SUMOylation and ubiquitination, leading to NDRG1 degradation. NDRG1 typically forms a complex with E-cadherin and β-catenin to suppress WNT signaling; however, this complex is disrupted by phosphorylation at the 346/356/366 sites. In vivo studies demonstrated that NDRG1 knockdown expedited tumor growth and pulmonary metastasis, but the re-expression of phosphorylation-deficient mutants, particularly at sites 328/330 and 346/356/366, significantly mitigated these tumor-promoting effects.</div><div>Our study demonstrates that hypoxia-induced C-terminal poly-phosphorylation of NDRG1 promotes its degradation, activating the WNT pathway and driving ccRCC malignancy. These findings underscore the role of NDRG1 phosphorylation in ccRCC progression under hypoxic conditions and highlight potential therapeutic targets for intervention.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"619 ","pages":"Article 217659"},"PeriodicalIF":9.1,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143704349","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cancer lettersPub Date : 2025-03-22DOI: 10.1016/j.canlet.2025.217662
Thomas Enzler , Timothy L. Frankel
{"title":"Pancreatic cancer precursor lesions – Can immunotherapy prevent progression into pancreatic ductal adenocarcinoma?","authors":"Thomas Enzler , Timothy L. Frankel","doi":"10.1016/j.canlet.2025.217662","DOIUrl":"10.1016/j.canlet.2025.217662","url":null,"abstract":"<div><div>Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers, with a 5-year survival rate of only 12.5 %. Early detection of PDAC or addressing risk factors for PDAC development are ways to improve outcomes. PDAC can arise from precursor lesions, including pancreatic intraepithelial neoplasia (PanIN), intraductal papillary mucinous neoplasm (IPMN), and less frequent, mucinous cystic neoplasm (MCN), and other rare precursor variants. High-risk precursor lesions harbor a substantial chance of evolving into PDAC. Such lesions can often be found in resected PDAC specimens adjacent to the cancer. Unfortunately, recognizing precursor lesions that need to be resected is often tricky, and resections frequently end in major surgical interventions. Thus, better ways to handle precursor lesions are desperately needed. We mapped the immune microenvironments (IMEs) of PanINs, IPMNs, and MCNs on a cellular level using multiplex immunofluorescence and computational imaging technology and compared the findings to PDACs and normal pancreatic tissues. We found distinct and potentially targetable mechanisms of immunosuppression between the two main precursor lesions, PanIN and IMPN. Immunosuppression in IPMNs seems partly mediated by programmed cell death protein 1 ligand (PD-L1) expression on antigen-presenting cells (APCs). By contrast, elevated numbers of regulatory T cells (Tregs) seem to be key players in the immunosuppression of PanINs. Thus, treating high-risk IPMNs with anti-PD-1 and high-risk PanINs with agents targeting Tregs, such as anti-lymphocyte associated protein 4 (anti-CTLA-4) antibodies, could reverse their immunosuppressive state. Reversal of immunosuppression will restore immunosurveillance and eventually prevent progression into PDAC. We also review relevant published and ongoing non-surgical treatment approaches for high-risk IPMNs and PanINs.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"619 ","pages":"Article 217662"},"PeriodicalIF":9.1,"publicationDate":"2025-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143699312","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cancer lettersPub Date : 2025-03-22DOI: 10.1016/j.canlet.2025.217668
Yasuaki Uemoto , Chang-Ching A. Lin , Bingnan Wang , Dan Ye , Yisheng V. Fang , Emmanuel Bikorimana , Fabiana Napolitano , Maria Rosario Chica-Parrado , Cheung Li , Saurabh Mendiratta , Chuo Chen , Ariella B. Hanker , Carlos L. Arteaga
{"title":"Selective degradation of FGFR1/2 overcomes antiestrogen resistance in ER+ breast cancer with FGFR1/2 alterations","authors":"Yasuaki Uemoto , Chang-Ching A. Lin , Bingnan Wang , Dan Ye , Yisheng V. Fang , Emmanuel Bikorimana , Fabiana Napolitano , Maria Rosario Chica-Parrado , Cheung Li , Saurabh Mendiratta , Chuo Chen , Ariella B. Hanker , Carlos L. Arteaga","doi":"10.1016/j.canlet.2025.217668","DOIUrl":"10.1016/j.canlet.2025.217668","url":null,"abstract":"<div><div><em>FGFR1</em> amplification and <em>FGFR1/2</em> activating mutations have been associated with antiestrogen resistance in estrogen receptor-positive (ER+) breast cancer. However, there are no approved FGFR1-targeted therapies for breast cancers harboring these alterations. In this study, we investigated the selective degradation of FGFR1/2 using the proteolysis-targeting chimera (PROTAC) DGY-09-192 as a novel therapeutic strategy in ER + breast cancers harboring <em>FGFR1/2</em> somatic alterations. Treatment of ER+/<em>FGFR1</em>-amplified breast cancer cells and patient-derived xenografts with DGY-09-192 resulted in sustained degradation of FGFR1 in a proteasome-dependent manner and suppressed downstream signal transduction. The combination of DGY-09-192 and the ERα degrader fulvestrant resulted in complete cell growth arrest and tumor regression of ER+/<em>FGFR1</em>-amplified patients-derived xenografts. In addition, we tested the effect of DGY-09-192 on breast cancer cells expressing <em>FGFR1</em><sup><em>N546K</em></sup> and <em>FGFR2</em><sup><em>K659E</em></sup> hotspot kinase domain mutations as well as ER-negative breast cancer cells harboring <em>FGFR2</em> gene amplification. Treatment with DGY-09-192 resulted in the degradation of mutant FGFR1/2 and blocked mutant receptor-induced signal transduction and antiestrogen resistance. Collectively, our study suggests that degradation of FGFR1/2, in combination with antiestrogens, can be leveraged as a therapeutic strategy in ER + breast cancers harboring <em>FGFR1/2</em> driver alterations.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"619 ","pages":"Article 217668"},"PeriodicalIF":9.1,"publicationDate":"2025-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143699315","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cancer lettersPub Date : 2025-03-22DOI: 10.1016/j.canlet.2025.217665
Maria M. Haykal , Sylvie Rodrigues-Ferreira , Rania El Botty , Laura Sourd , Elisabetta Marangoni , Marie Varin , Alexis Denis , Clara Nahmias
{"title":"Targeting WEE1 kinase as a therapeutic strategy in ATIP3-deficient breast cancers","authors":"Maria M. Haykal , Sylvie Rodrigues-Ferreira , Rania El Botty , Laura Sourd , Elisabetta Marangoni , Marie Varin , Alexis Denis , Clara Nahmias","doi":"10.1016/j.canlet.2025.217665","DOIUrl":"10.1016/j.canlet.2025.217665","url":null,"abstract":"<div><div>ATIP3-deficient breast cancers represent a subset of aggressive tumors with limited therapeutic options and poor prognosis. Here, we screened a panel of cell cycle kinase inhibitors to identify novel targets for these tumors. We show that loss of ATIP3 sensitizes breast cancer cells to WEE1 inhibition, resulting in aberrant mitoses characterized by detachment of centromere proteins from DNA and chromosome pulverization. This phenotype arises from excessive replication stress and DNA damage in S-phase, combined with premature mitotic entry driven by untimely CDK1 activation. Mechanistically, we identify DNA2 helicase/nuclease as a key mediator of chromosome pulverization. Importantly, the heightened sensitivity of ATIP3-deficient cells to WEE1 inhibition provides a strong rationale for clinical exploration of WEE1-targeted therapies. Furthermore, combining WEE1 and PKMYT1 inhibitors enhances therapeutic efficacy, offering a promising strategy for personalized treatment in ATIP3-deficient breast cancers.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"620 ","pages":"Article 217665"},"PeriodicalIF":9.1,"publicationDate":"2025-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143699495","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cancer lettersPub Date : 2025-03-22DOI: 10.1016/j.canlet.2025.217647
Advaitha Midde , Navpreet Arri , Tibor Kristian , Suprabhat Mukherjee , Parth Sarthi Sen Gupta , Yuji Zhang , Mariuz Karbowski , Jaylyn Waddell , Nagarajan Maharajan , Md Sazzad Hassan , Heather M. O'Hagan , Michal Zalzman , Aditi Banerjee
{"title":"Targeting mitochondrial ribosomal protein expression by andrographolide and melatonin for colon cancer treatment","authors":"Advaitha Midde , Navpreet Arri , Tibor Kristian , Suprabhat Mukherjee , Parth Sarthi Sen Gupta , Yuji Zhang , Mariuz Karbowski , Jaylyn Waddell , Nagarajan Maharajan , Md Sazzad Hassan , Heather M. O'Hagan , Michal Zalzman , Aditi Banerjee","doi":"10.1016/j.canlet.2025.217647","DOIUrl":"10.1016/j.canlet.2025.217647","url":null,"abstract":"<div><div>Colospheroids contain colon cancer stem cells (CSCs) that cause colorectal cancer metastasis (mCRC). Colorectal cancer (CRC) is the second leading cause of cancer-related deaths in the U.S. Little is known about the role of mitochondria in the survival and metastatic ability of CSCs. In this study, we investigate the effect of andrographolide (AGP) and melatonin (MLT) on mitochondrial dynamics (including fusion and fission) and the expression of mitochondrial ribosomal proteins (MRPs). Our results show that AGP and MLT synergistically reduce the total active mitochondrial mass, downregulate fusion and fission proteins, reduce OXPHOS proteins, and lead to CSC growth inhibition via Nrf2 and KEAP1 signaling. Microarray revealed 4389 differentially expressed mRNAs in the AGP and MLT combination compared to the control. Results exhibiting a three-fold induction/reduction were validated by qRT-PCR and immunoblot. MRPS6, a mitochondrial ribosomal (Mitoribosome) small subunit protein, was dramatically downregulated by AGP + MLT treatment compared to control. MRPS6 inhibition by siRNA reduced mCRC cell viability. Molecular docking-based protein-ligand interactions showed that AGP has direct physical interaction with MRPS6 and increases the binding affinity of MLT to MRPS6. This drug combination downregulated genes in the NRF2 (NFE2L2) pathway in CSCs. MRPS6 may be directly linked to CSC proliferation and could be a therapeutic target for this population. Functionally, MRPS6 knockdown significantly reduced colony formation, with enhanced suppression in AGP + MLT-treated cells. In xenograft models, the AGP-MLT combination synergistically decreased MRPS6 expression and increased apoptosis, as evidenced by TUNEL assays, demonstrating the therapeutic potential of targeting MRPS6 in CRC.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"619 ","pages":"Article 217647"},"PeriodicalIF":9.1,"publicationDate":"2025-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143699492","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}