Oncogenesis最新文献_第8页

GlycoRNAs are abundant in glioma and involved in glioma cell proliferation. glycorna在胶质瘤中含量丰富，参与胶质瘤细胞的增殖。

IF 6.4 2区医学

Oncogenesis Pub Date : 2025-10-01 DOI: 10.1038/s41389-025-00570-5

Benkai Xin, Jiajun Chen, Xin Hu, Jingtong Yang, Xiaoyu Wang, Ziqian Wang, Youzhong Wan, Lin Wang

{"title":"GlycoRNAs are abundant in glioma and involved in glioma cell proliferation.","authors":"Benkai Xin, Jiajun Chen, Xin Hu, Jingtong Yang, Xiaoyu Wang, Ziqian Wang, Youzhong Wan, Lin Wang","doi":"10.1038/s41389-025-00570-5","DOIUrl":"10.1038/s41389-025-00570-5","url":null,"abstract":"Recent studies have identified glycosylated RNAs (glycoRNAs) as a novel class of biomolecules potentially involved in cancers and immunological diseases. However, their presence and functional roles in glioma remain unexplored. GlycoRNAs were extracted from glioma cells and detected using Ac4ManNAz labeling and Northern blot. Small RNA deep sequencing and qRT-PCR were employed to determine RNA types and content. A sequence-specific RNA-capture magnetic bead system was developed to enrich specific glycoRNAs, such as U2 and U4. Glycan components were analyzed using liquid chromatography-mass spectrometry. CCK-8, adhesion, ki67, TUNEL staining assays were used to evaluate cell viability, adhesion, proliferation and apoptosis. Glioma cells were found to be rich in glycoRNAs, predominantly small RNAs, with U2 and U4 being particularly abundant. These glycoRNAs primarily contained fucosylated and sialylated complex glycans. The depletion of cell-surface glycoRNAs at the observed time point significantly inhibited glioma cell viability and proliferation, without altering cell adhesion or apoptosis levels. This study underscored the significant role of glycoRNAs in glioma proliferation and provided a foundation for further research into their potential as novel biomarkers and therapeutic targets for glioma. Glioma cells U87 and LN229 showed significant enrichment in glycoRNAs, predominantly small RNAs, with U2 and U4 being particularly abundant and specific. Furthermore, these glycoRNAs were found to be modified by multiple glycans, primarily complex, fucosylated, and sialylated structures.","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":"14 1","pages":"29"},"PeriodicalIF":6.4,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12484618/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145200520","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Targeting pregnane X receptor with a potent agonist-based PROTAC to delay colon cancer relapse. 基于PROTAC的强效激动剂靶向妊娠X受体延缓结肠癌复发。

IF 6.4 2区医学

Oncogenesis Pub Date : 2025-08-30 DOI: 10.1038/s41389-025-00573-2

Lucile Bansard, Guillaume Laconde, Vanessa Delfosse, Tiphaine Huet, Margaux Ayeul, Emilie Rigal, Quentin Donati, Sabine Gerbal-Chaloin, Martine Daujat-Chavanieu, Luc Brunel, Baptiste Legrand, Alain Chavanieu, Anthony R Martin, Julie Pannequin, William Bourguet, Muriel Amblard, Jean Marc Pascussi

{"title":"Targeting pregnane X receptor with a potent agonist-based PROTAC to delay colon cancer relapse.","authors":"Lucile Bansard, Guillaume Laconde, Vanessa Delfosse, Tiphaine Huet, Margaux Ayeul, Emilie Rigal, Quentin Donati, Sabine Gerbal-Chaloin, Martine Daujat-Chavanieu, Luc Brunel, Baptiste Legrand, Alain Chavanieu, Anthony R Martin, Julie Pannequin, William Bourguet, Muriel Amblard, Jean Marc Pascussi","doi":"10.1038/s41389-025-00573-2","DOIUrl":"10.1038/s41389-025-00573-2","url":null,"abstract":"Tumor recurrence is frequently attributed to drug-tolerant cancer cells. We previously demonstrated that downregulation of the Pregnane X Receptor (PXR, NR1I2) reduces chemoresistance and prevents colorectal cancer recurrence in xenograft mouse models. However, there is currently a lack of clinically-suitable PXR antagonists. In this study, we report the design and synthesis of a novel PXR agonist-based PROTAC (JMV7048) which promotes polyubiquitination and degradation of the human PXR protein via E3 CRBN ubiquitin ligase and 26S proteasome pathways. JMV7048 selectively degrades PXR in colon carcinoma, hepatoma, and pancreatic cancer cell lines, with no impact on primary human hepatocytes. Notably, JMV7048 reduces PXR protein expression in drug-tolerant colon cancer cells, sensitizing them to chemotherapy and significantly delaying cancer relapse in xenografted nude mice. These findings suggest that PXR-targeting PROTACs may serve as novel therapeutic agents to enhance the sensitivity of chemo-resistant cancer cells to chemotherapy.","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":"14 1","pages":"34"},"PeriodicalIF":6.4,"publicationDate":"2025-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12398506/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144963610","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A dominant SRCAP truncating mutation promotes squamous cell carcinoma progression. 显性SRCAP截断突变促进鳞状细胞癌的进展。

IF 6.4 2区医学

Oncogenesis Pub Date : 2025-08-26 DOI: 10.1038/s41389-025-00576-z

Stephenie H Droll, Elena I O Dewar, Celia Xue, Max C Levine, Benny J Zhang, Xiaomin Bao

{"title":"A dominant SRCAP truncating mutation promotes squamous cell carcinoma progression.","authors":"Stephenie H Droll, Elena I O Dewar, Celia Xue, Max C Levine, Benny J Zhang, Xiaomin Bao","doi":"10.1038/s41389-025-00576-z","DOIUrl":"10.1038/s41389-025-00576-z","url":null,"abstract":"The majority of life-threatening cancers arise from epithelial tissues. These epithelial cancers include cutaneous squamous cell carcinoma (cSCC), the second-most common cancer. cSCC is highly invasive and accounts for an estimated 15,000 deaths each year. We identified SRCAP, a chromatin remodeler that regulates the chromatin occupancy of the histone H2A variant H2A.Z, as a frequently mutated gene in cSCC. Analysis of cSCC mutations in epithelial cancers identified a hotspot truncating mutation in SRCAP, which removes 42% of the protein sequences after amino acid 1879. While SRCAP mutations have been previously connected to the pathogenesis of Floating-Harbor syndrome (FHS), these typically occur downstream, with a hotspot mutation leading to protein truncation after amino acid 2444. We found that expressing the SRCAP-1879 truncation in an HRas-CDK4-driven cSCC model was sufficient to increase proliferation, impair terminal differentiation, and accelerate invasion. Mechanistically, the expression of SRCAP-1879 in primary human keratinocytes was sufficient to dysregulate genes crucial for carcinogenesis (e.g., proliferation, differentiation, and motility) without altering H2A.Z occupancy. In particular, the expression of SRCAP-1879 truncation led to strong induction of the matrix metalloproteinase MMP9 expression level, accompanied by increased keratinocyte cell motility, which was sensitive to matrix metalloprotease inhibition. In contrast, the expression of the SRCAP-FHS truncation did not increase but instead reduced cell motility as well as the expression of MMP9. Taken together, our findings identify a previously under-characterized role of the SRCAP-1879 truncating mutation in promoting multiple aspects of epithelial cancer progression, including invasion, distinct from the well-recognized roles of SRCAP mutations in FHS pathogenesis.","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":"14 1","pages":"33"},"PeriodicalIF":6.4,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12381255/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144963643","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

BRG1 inhibits glycolysis by promoting SHP1-mediated dephosphorylation of PKM2 in non-small cell lung cancer. 在非小细胞肺癌中，BRG1通过促进shp1介导的PKM2去磷酸化来抑制糖酵解。

IF 6.4 2区医学

Oncogenesis Pub Date : 2025-08-24 DOI: 10.1038/s41389-025-00577-y

Wenli Zhan, Haokun Zhang, Xiaowei She, Genshan Zhang, Jiakun Zhang, Xuelai Luo, Haijie Li, Jingqin Lan

引用次数: 0

Peroxisomal lipid metabolism inhibits Pimozide-induced cancer cell death by regulating ATP homeostasis. 过氧化物酶体脂质代谢通过调节ATP稳态抑制吡莫齐特诱导的癌细胞死亡。

IF 6.4 2区医学

Oncogenesis Pub Date : 2025-08-21 DOI: 10.1038/s41389-025-00575-0

Zihang Pan, Fazhi Yu, Weiyi You, Feng Li, Fengjuan Cui, Jing Guo, Zhenye Yang

{"title":"Peroxisomal lipid metabolism inhibits Pimozide-induced cancer cell death by regulating ATP homeostasis.","authors":"Zihang Pan, Fazhi Yu, Weiyi You, Feng Li, Fengjuan Cui, Jing Guo, Zhenye Yang","doi":"10.1038/s41389-025-00575-0","DOIUrl":"10.1038/s41389-025-00575-0","url":null,"abstract":"Antipsychotic drugs have been shown to suppress tumor growth and induce cell death, but their clinical application remains limited. Pimozide, an FDA-approved antipsychotic, holds significant potential for cancer treatment. However, the mechanisms underlying tumor cell responses to Pimozide remain unclear. In this study, we identify a critical role for peroxisomes in mediating tumor cell resistance to Pimozide. Our findings demonstrate that Pimozide increases peroxisome numbers and that peroxisomal deficiency significantly enhances Pimozide-induced cell death. We show that peroxisomes mitigate Pimozide-induced apoptosis primarily through fatty acid oxidation and ether lipid synthesis, rather than reactive oxygen species (ROS) metabolism. Moreover, Pimozide treatment upregulates peroxisomal lipid-metabolizing enzymes in tumor cells. As key metabolic hubs interconnected with mitochondrial metabolism, peroxisomes support energy homeostasis, thereby preventing Pimozide-induced cell death. These findings underscore the importance of peroxisomes in maintaining mitochondrial morphology and cellular energy homeostasis, offering novel insights into the potential therapeutic applications of Pimozide in cancer treatment.","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":"14 1","pages":"31"},"PeriodicalIF":6.4,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12371041/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144963626","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Targeting macrophage migration inhibitory factor as a potential therapeutic strategy in colorectal cancer. 靶向巨噬细胞迁移抑制因子作为结直肠癌的潜在治疗策略。

IF 6.4 2区医学

Oncogenesis Pub Date : 2025-08-20 DOI: 10.1038/s41389-025-00572-3

Kim Lucia Schneider, Luisa Claus, Richard Bucala, Ramona Schulz-Heddergott

{"title":"Targeting macrophage migration inhibitory factor as a potential therapeutic strategy in colorectal cancer.","authors":"Kim Lucia Schneider, Luisa Claus, Richard Bucala, Ramona Schulz-Heddergott","doi":"10.1038/s41389-025-00572-3","DOIUrl":"10.1038/s41389-025-00572-3","url":null,"abstract":"Survival rates for patients with late-stage colorectal cancer (CRC) remain low due to limited efficacy of current therapeutic regimens. To overcome these challenges, novel drug targets are urgently needed. Macrophage migration inhibitory factor (MIF), an upstream immunoregulatory cytokine, has emerged as a potential target due to its multifaceted role in cancer pathogenesis. During tumorigenesis, MIF protein levels are often elevated in tumor cells through chaperone-mediated stabilization. Although several in vivo studies have implicated MIF in tumor initiation and progression, its role in sustaining established tumors, particularly when derived from epithelial tumor cells, remained unclear. Using a constitutive Mif knockout mouse model, we previously demonstrated that MIF is required for CRC development. Now, we expanded our experimental CRC model towards a more therapeutic rationale. We hypothesized that epithelial-derived MIF is essential for tumor maintenance and might serve as a possible cancer drug target. Therefore, we depleted epithelial MIF during late-stage CRC tumorigenesis in two genetically-engineered and chemically-induced murine CRC models. Our proof-of-principle study reveals that Mif depletion in epithelial tumor cells attenuates cancer maintenance in both CRC models, coinciding with reduced macrophage recruitment and angiogenesis. Our data highlight the potential utility of targeting MIF in CRC patients for therapeutic benefit.","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":"14 1","pages":"30"},"PeriodicalIF":6.4,"publicationDate":"2025-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12368102/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144963553","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Inhibition of LDHB triggers DNA damage and increases cisplatin sensitivity in pleural mesothelioma. 抑制LDHB触发DNA损伤并增加胸膜间皮瘤的顺铂敏感性。

IF 6 2区医学

Oncogenesis Pub Date : 2025-08-11 DOI: 10.1038/s41389-025-00571-4

Yantang Lin, Christelle Dubey, Tereza Losmanova, Samuel Oevgü Yasmin, Jean-Louis Reymond, Ren-Wang Peng, Haibin Deng, Patrick Dorn, Thomas Michael Marti

{"title":"Inhibition of LDHB triggers DNA damage and increases cisplatin sensitivity in pleural mesothelioma.","authors":"Yantang Lin, Christelle Dubey, Tereza Losmanova, Samuel Oevgü Yasmin, Jean-Louis Reymond, Ren-Wang Peng, Haibin Deng, Patrick Dorn, Thomas Michael Marti","doi":"10.1038/s41389-025-00571-4","DOIUrl":"10.1038/s41389-025-00571-4","url":null,"abstract":"Pleural mesothelioma (PM) is an aggressive, asbestos-linked cancer with limited treatment options and a poor prognosis. Lactate dehydrogenase B (LDHB) converts lactate to pyruvate, and its silencing reduces mitochondrial metabolism, particularly nucleotide synthesis. However, whether and a role of LDHB in PM is unclear. This study aimed to investigate the effects of silencing LDHB in PM cells and their response to chemotherapy. LDHB was silenced using siRNA transfection and inducible shRNA constructs. Proliferation, colony formation, and cell viability were assessed, while DNA damage was analyzed through ɣH2AX levels. Compared to normal mesothelial cells, LDHB was highly expressed in PM cell lines. LDHB inhibition significantly reduced proliferation, cell viability, and colony formation, indicating its crucial role in PM cells. Additionally, LDHB silencing significantly increased nuclear DNA damage accumulation as indicated by elevated ɣH2AX levels, which was reversed by nucleotide supplementation. In vivo, LDHB inhibition reduced tumor growth and enhanced cisplatin's therapeutic efficacy. LDHB silencing increased ɣH2AX levels, which were further elevated with cisplatin treatment. Our results highlight LDHB as a novel therapeutic target in PM, where its inhibition induces DNA damage and improves the efficacy of cisplatin therapy.","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":"14 1","pages":"28"},"PeriodicalIF":6.0,"publicationDate":"2025-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12340043/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144822106","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Novel CDK2/CDK9 inhibitor fadraciclib targets cell survival and DNA damage pathways and synergizes with encorafenib in human colorectal cancer cells with BRAF(V600E). 新型CDK2/CDK9抑制剂fadraciclib靶向BRAF（V600E）人结直肠癌细胞的细胞存活和DNA损伤途径，并与encorafenib协同作用。

IF 6.4 2区医学

Oncogenesis Pub Date : 2025-08-06 DOI: 10.1038/s41389-025-00574-1

Md Mohiuddin, Vanda Póvoa, Rita Fior, Frank A Sinicrope

{"title":"Novel CDK2/CDK9 inhibitor fadraciclib targets cell survival and DNA damage pathways and synergizes with encorafenib in human colorectal cancer cells with BRAF(V600E).","authors":"Md Mohiuddin, Vanda Póvoa, Rita Fior, Frank A Sinicrope","doi":"10.1038/s41389-025-00574-1","DOIUrl":"10.1038/s41389-025-00574-1","url":null,"abstract":"The oncogenic BRAF(V600E) mutation activates the ERK1/2 pathway and is detected in 10% of human colorectal cancers (CRCs) where it is associated with poor prognosis. Inhibitors of BRAF have shown only modest efficacy in patients with CRC due to intrinsic drug resistance. We studied the CDK2/CDK9 inhibitor, fadraciclib, alone and in combination with the BRAF inhibitor encorafenib in isogenic human RKO CRC cells with two, one, or no BRAFV600E alleles (RKO+/+, A19+/-, T29-/-) and in BRAF wild-type HCT-116 cells, including Bax knockout HCT-116Bax-/- cells. Treatment with fadraciclib was shown to suppress MCL-1 and phospho-MCL-1 (Ser64), induce a Bax-dependent apoptosis, and inhibit colony formation in a BRAF gene dose-dependent manner. Fadraciclib decreased phosphorylation of RNA polymerase II, indicating suppression of RNA transcription. The tumor growth inhibitory effect of fadraciclib plus encorafenib was synergistic. Fadraciclib decreased Rb phosphorylation, inhibited cell cycle progression, and promoted DNA damage as evidenced by cleavage of PARP, increased pH2AX (ser139), and activation of p53. In RKO+/+ versus A19+/- or T29-/- cells, drug treatment was associated with greater suppression of p-Rb and inhibition of apoptosis and the cell cycle. In a zebrafish xenograft model, fadraciclib plus encorafenib significantly reduced tumor size, concurrent with increased caspase-3 activation. In human CRCs, BRAF mutation was associated with overexpression of CDK2, and CDK9 overexpression was associated with worse patient survival. In conclusion, fadraciclib depletes MCL-1 to potentiate apoptosis and, combined with encorafenib, synergistically suppresses tumor cell growth in a BRAFV600E gene dose-dependent manner. These data suggest a novel therapeutic strategy in CRCs with BRAFV600E.","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":"14 1","pages":"27"},"PeriodicalIF":6.4,"publicationDate":"2025-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12329046/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144794944","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Targeting SLC7A5 in lung squamous cell carcinoma: implications for cancer metabolism shift and boron neutron capture therapy resistance. 靶向SLC7A5治疗肺鳞状细胞癌：癌症代谢转移和硼中子俘获治疗耐药的意义

IF 5.9 2区医学

Oncogenesis Pub Date : 2025-07-23 DOI: 10.1038/s41389-025-00568-z

Yen-Ju Lin, Yu-Cheng Wu, Yu-Jui Liu, Wei-Chen Yeh, Yi-Chen Huang, Shen-Ao Zhang, Alvin Chen, Ming-Yi Zheng, Hong-Ming Liu, Fong-In Chou, Shien-Tung Pan, Min-Yuan Chou, Yu-Ting Chou

{"title":"Targeting SLC7A5 in lung squamous cell carcinoma: implications for cancer metabolism shift and boron neutron capture therapy resistance.","authors":"Yen-Ju Lin, Yu-Cheng Wu, Yu-Jui Liu, Wei-Chen Yeh, Yi-Chen Huang, Shen-Ao Zhang, Alvin Chen, Ming-Yi Zheng, Hong-Ming Liu, Fong-In Chou, Shien-Tung Pan, Min-Yuan Chou, Yu-Ting Chou","doi":"10.1038/s41389-025-00568-z","DOIUrl":"10.1038/s41389-025-00568-z","url":null,"abstract":"Squamous cell carcinoma (SCC) poses a significant global health challenge due to the lack of effective treatments. Boron neutron capture therapy (BNCT), a targeted particle therapy, has shown promising results in various cancers. SLC7A5, a transporter of essential amino acids and boronophenylalanine (BPA) used in BNCT, emerges as a potential therapeutic target. However, its expression across different histological subtypes and the role of SLC7A5 inhibition in developing drug resistance to BPA-BNCT remain poorly understood. Our study reveals elevated SLC7A5 expression in most SCCs, particularly in lung squamous cell carcinoma (LUSC), where it is significantly higher compared to other lung cancer subtypes. Increased SLC7A5 expression and a higher tumor-to-normal (T/N) ratio in LUSC are associated with poor patient prognosis. SLC7A5 knockdown in LUSC cells reduces colony formation and induces apoptosis. RNA-seq analysis of SLC7A5 knockout LUSC cells shows downregulated mTORC1 signaling, reduced expression of other amino acid transporters, and upregulated autophagy genes, indicating a potential cancer metabolic shift. Furthermore, SLC7A5 knockout LUSC cells demonstrate resistance to BPA-BNCT but sensitivity to the autophagy inhibitor chloroquine. Post-BPA-BNCT treatment, surviving wild-type LUSC cells exhibit reduced SLC7A5 levels and increased sensitivity to chloroquine, highlighting a vulnerability in BPA-BNCT-resistant cells. Our findings elucidate the interplay between SLC7A5, mTOR signaling, and autophagy pathways, providing insights into potential strategies to overcome drug resistance in BPA-BNCT therapy.","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":"14 1","pages":"26"},"PeriodicalIF":5.9,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12287270/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144699182","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

GSK-3 and BCL-XL inhibition mitigates the competitive advantage of APC-mutant colorectal cancer cells. GSK-3和BCL-XL抑制降低了apc突变型结直肠癌细胞的竞争优势。

IF 5.9 2区医学

Oncogenesis Pub Date : 2025-07-13 DOI: 10.1038/s41389-025-00569-y

Le Zhang, Lidia Atencia Taboada, Selami Baglamis, Maartje de Kroon, Carolien Elshout, Prashanthi Ramesh, Roxan F C P A Helderman, Arezo Torang, Kate Cameron, Milou S van Driel, Valérie M Wouters, Sanne M van Neerven, Jan Paul Medema

{"title":"GSK-3 and BCL-XL inhibition mitigates the competitive advantage of APC-mutant colorectal cancer cells.","authors":"Le Zhang, Lidia Atencia Taboada, Selami Baglamis, Maartje de Kroon, Carolien Elshout, Prashanthi Ramesh, Roxan F C P A Helderman, Arezo Torang, Kate Cameron, Milou S van Driel, Valérie M Wouters, Sanne M van Neerven, Jan Paul Medema","doi":"10.1038/s41389-025-00569-y","DOIUrl":"10.1038/s41389-025-00569-y","url":null,"abstract":"BCL-XL is a crucial anti-apoptotic protein that supports survival of intestinal cells during the progression and in established colorectal cancer (CRC). While targeting BCL-XL with BH3 mimetics is effective, its significant toxicity highlights the need for alternative approaches. Importantly, the early steps in intestinal transformation are marked by a competition between normal and transformed stem cells in which the mutant cells gain a supercompetitive advantage due to the secretion of WNT inhibitors. Using multiple human and murine CRC models, we revealed that GSK-3 inhibition strongly sensitized to BH3 mimetic-induced killing. As expected, GSK-3 inhibition significantly upregulated the WNT pathway, but also led to marked enhancement of BH3 mimetic-induced apoptosis, as measured by mitochondrial BAX aggregation, Caspase-3 activation and Propidium Iodide exclusion. Furthermore, GSK-3 inhibition provided an advantage to wild-type intestinal organoids in competition with APC-mutant counterparts due to reactivation of the WNT pathway. More strikingly, combining GSK-3 and BCL-XL inhibition profoundly affected the supercompetition APC-mutant intestinal cells exert over the wild-types. In effect, the combination therapy enhanced the competitive fitness of wild-type cells and resulted in the killing of APC-mutant organoids, pointing to a novel combination therapy that can be further exploited in the treatment of adenomas and CRC.","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":"14 1","pages":"25"},"PeriodicalIF":5.9,"publicationDate":"2025-07-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12255667/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144619705","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0