Cell Death Discovery最新文献_第10页

GTPase GPN3 facilitates cell proliferation and migration in non-small cell lung cancer by impeding clathrin-mediated endocytosis of EGFR.

IF 6.1 2区生物学

Cell Death Discovery Pub Date : 2025-02-01 DOI: 10.1038/s41420-025-02317-y

Linlin Xu, Jiankun Guo, Xinsheng Xie, Hailong Wang, Alan Jiang, Changhua Huang, Hua Yang, Shiwen Luo, Limin Chen

{"title":"GTPase GPN3 facilitates cell proliferation and migration in non-small cell lung cancer by impeding clathrin-mediated endocytosis of EGFR.","authors":"Linlin Xu, Jiankun Guo, Xinsheng Xie, Hailong Wang, Alan Jiang, Changhua Huang, Hua Yang, Shiwen Luo, Limin Chen","doi":"10.1038/s41420-025-02317-y","DOIUrl":"10.1038/s41420-025-02317-y","url":null,"abstract":"Small GTPases play a critical role as regulatory molecules in signaling transduction and various cellular processes, contributing to the development of human diseases, including cancers. GPN3, an evolutionarily conserved member of the GPN-loop GTPase subfamily classified in 2007 according to its structure, has limited knowledge regarding its cellular functions and molecular mechanisms. In this study, we demonstrate that GPN3 interacts with clathrin light chain A (CLTA), a vesicle coat protein, as well as clathrin-mediated endocytosis associated modulators AP2B1 and AP2S1. Upregulation of GPN3 leads to the inhibition of clathrin-coated pit invagination. Furthermore, we discovered that GPN3 interacts with the epidermal growth factor receptor (EGFR) and regulates the co-localization of EGFR and CLTA, as well as the localization of EGFR in early endosomes upon EGF stimulation. As a result, this leads to a decrease in endocytic levels of EGFR and an increase in the accumulation of EGFR on the cell membrane surface, thereby prolonging activation of EGFR signaling. The functional effects exerted by GPN3 are dependent on cellular levels of GTP abundance. Furthermore, our findings indicate that aberrant overexpression of GPN3 is observed in non-small cell lung cancer (NSCLC) tissues compared to adjacent normal tissues, and high expression levels of GPN3 are associated with poor prognosis for NSCLC patients. Collectively, these findings reveal that GPN3 acts as an oncogene promoting cell proliferation and migration in NSCLC through regulation of clathrin-dependent EGFR endocytosis. These results suggest that targeting GPN3 could serve as a novel prognostic biomarker and therapeutic strategy for NSCLC treatment.","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"38"},"PeriodicalIF":6.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11787391/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143073950","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Regulatory roles of RNA binding proteins in the Hippo pathway.

IF 6.1 2区生物学

Cell Death Discovery Pub Date : 2025-01-31 DOI: 10.1038/s41420-025-02316-z

Shuchang Peng, Chenglin Li, Yanwen He, Lei Xue, Xiaowei Guo

引用次数: 0

The crosstalk between SND1 and PDCD4 is associated with chemoresistance of non-small cell lung carcinoma cells.

IF 6.1 2区生物学

Cell Death Discovery Pub Date : 2025-01-30 DOI: 10.1038/s41420-025-02310-5

Yun Zhao, Shanel Dhani, Vladimir Gogvadze, Boris Zhivotovsky

{"title":"The crosstalk between SND1 and PDCD4 is associated with chemoresistance of non-small cell lung carcinoma cells.","authors":"Yun Zhao, Shanel Dhani, Vladimir Gogvadze, Boris Zhivotovsky","doi":"10.1038/s41420-025-02310-5","DOIUrl":"10.1038/s41420-025-02310-5","url":null,"abstract":"Lung cancer is the leading cause of cancer-related deaths worldwide. Non-small cell lung cancer (NSCLC) is highly resistant to chemo- or radiation therapy, which poses a huge challenge for treatment of advanced NSCLC. Previously, we demonstrated the oncogenic role of Tudor Staphylococcal nuclease (TSN, also known as Staphylococcal nuclease domain-containing protein 1, SND1), in regulating chemoresistance in NSCLC cells. Here, we showed that silencing of SND1 augmented the sensitivity of NSCLC cells to different chemotherapeutic drugs. Additionally, the expression of PDCD4 (a tumor suppressor highly associated with lung cancer) in NSCLC cells with low endogenous levels was attenuated by SND1 silencing, implying that SND1 might function as a molecular regulator upstream of PDCD4. PDCD4 is differentially expressed in various NSCLC cells. In the NSCLC cells (A549 and H23 cells) with low expression of PDCD4, despite the downregulation of PDCD4, silencing of SND1 still led to sensitization of NSCLC cells to treatment with different chemotherapeutic agents by the inhibition of autophagic activity. Thus, a novel correlation interlinking SND1 and PDCD4 in the regulation of NSCLC cells concerning chemotherapy was revealed, which contributes to understanding the mechanisms of chemoresistance in NSCLC.","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"34"},"PeriodicalIF":6.1,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11782486/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143063986","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

PARP4 deficiency enhances sensitivity to ATM inhibitor by impairing DNA damage repair in melanoma.

IF 6.1 2区生物学

Cell Death Discovery Pub Date : 2025-01-30 DOI: 10.1038/s41420-025-02296-0

Yuehua Li, Yu Liu, Jingjing Ma, Yuqi Yang, Qiao Yue, Guannan Zhu, Weinan Guo, Tianwen Gao, Qiong Shi, Chunying Li

{"title":"PARP4 deficiency enhances sensitivity to ATM inhibitor by impairing DNA damage repair in melanoma.","authors":"Yuehua Li, Yu Liu, Jingjing Ma, Yuqi Yang, Qiao Yue, Guannan Zhu, Weinan Guo, Tianwen Gao, Qiong Shi, Chunying Li","doi":"10.1038/s41420-025-02296-0","DOIUrl":"10.1038/s41420-025-02296-0","url":null,"abstract":"Besides the important pathogenic mechanisms of melanoma, including BRAF-driven and immunosuppressive microenvironment, genomic instability and abnormal DNA double-strand breaks (DSB) repair are significant driving forces for its occurrence and development. This suggests investigating novel therapeutic strategies from the synthetic lethality perspective. Poly (ADP-ribose) polymerase 4 (PARP4) is known to be a member of the PARP protein family. The low expression of PARP4 is significantly associated with defective DSB repair markers and poor prognosis in melanoma. Further research revealed that PARP4 plays a role in DSB repair by regulating the non-homologous end joining (NHEJ) pathway through its involvement in Ku80 mono-ADP-ribosylation. Moreover, from a synthetic lethality perspective, PARP4 expression is associated with ATM inhibitor sensitivity. Overall, our study provides new and valuable insights into the function of PARP4 and melanoma pathogenesis and suggests that ATM inhibitor may be a promising therapeutic approach for treating melanoma with low PARP4 expression.","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"35"},"PeriodicalIF":6.1,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11782537/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143063958","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","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 ferroptosis: a promising approach for treating lung carcinoma.

IF 6.1 2区生物学

Cell Death Discovery Pub Date : 2025-01-29 DOI: 10.1038/s41420-025-02308-z

Ziyang Wu, Yan Zhang, Wendi Zhong, Kunjian Wu, Tian Zhong, Tao Jiang

{"title":"Targeting ferroptosis: a promising approach for treating lung carcinoma.","authors":"Ziyang Wu, Yan Zhang, Wendi Zhong, Kunjian Wu, Tian Zhong, Tao Jiang","doi":"10.1038/s41420-025-02308-z","DOIUrl":"10.1038/s41420-025-02308-z","url":null,"abstract":"Lung carcinoma incidence and fatality rates remain among the highest on a global scale. The efficacy of targeted therapies and immunotherapies is commonly compromised by the emergence of drug resistance and other factors, resulting in a lack of durable therapeutic benefits. Ferroptosis, a distinct pattern of cell death marked by the buildup of iron-dependent lipid peroxides, has been shown to be a novel and potentially more effective treatment for lung carcinoma. However, the mechanism and regulatory network of ferroptosis are exceptionally complex, and many unanswered questions remain. In addition, research on ferroptosis in the diagnosis and treatment of lung cancer has been growing exponentially. Therefore, it is necessary to provide a thorough summary of the latest advancements in the field of ferroptosis. Here, we comprehensively analyze the mechanisms underlying the preconditions of ferroptosis, the defense system, and the associated molecular networks. The potential strategies of ferroptosis in the treatment of lung carcinoma are also highlighted. Targeting ferroptosis improves tumor cell drug resistance and enhances the effectiveness of targeted drugs and immunotherapies. These findings may shed fresh light on the diagnosis and management of lung carcinoma, as well as the development of drugs related to ferroptosis.","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"33"},"PeriodicalIF":6.1,"publicationDate":"2025-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11775225/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143058066","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","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 Y178C rhodopsin mutation causes aggregation and comparatively severe retinal degeneration.

IF 6.1 2区生物学

Cell Death Discovery Pub Date : 2025-01-29 DOI: 10.1038/s41420-025-02311-4

Sreelakshmi Vasudevan, Paul S-H Park

{"title":"A Y178C rhodopsin mutation causes aggregation and comparatively severe retinal degeneration.","authors":"Sreelakshmi Vasudevan, Paul S-H Park","doi":"10.1038/s41420-025-02311-4","DOIUrl":"10.1038/s41420-025-02311-4","url":null,"abstract":"Rhodopsin is the light-activated G protein-coupled receptor that initiates vision in photoreceptor cells of the retina. Numerous mutations in rhodopsin promote receptor misfolding and aggregation, causing autosomal dominant retinitis pigmentosa, a progressive retinal degenerative disease. The mechanism by which these mutations cause photoreceptor cell death, and the role aggregation plays in this process is still unclear. We recently demonstrated with the P23H and G188R rhodopsin mutants that the severity of aggregation observed in vitro is also reflected in vivo and impacts the rate of retinal degeneration. A Y178C rhodopsin mutant was investigated here to determine if this relationship applies broadly among mutations that cause misfolding and aggregation of the receptor. In vitro characterization indicated the Y178C rhodopsin mutant exhibits similar properties to the more severely aggregating G188R rhodopsin mutant, where the mutant is mislocalized to the endoplasmic reticulum in HEK293 cells and form aggregates that cannot be rescued by treatment with the retinoid 9-cis retinal. Despite these similarities in vitro, the Y178C rhodopsin mutant promoted a more severe retinal degeneration compared to the G188R mutant in vivo in mice. Aggregates of the Y178C rhodopsin mutant labeled by the dye PROTEOSTAT were morphologically similar to those formed by both the P23H and G188R rhodopsin mutants. There was, however, significantly greater photoreceptor cell death occurring independently of PROTEOSTAT-labeled aggregates in mice expressing the Y178C rhodopsin mutant compared to those expressing either the P23H or G188R rhodopsin mutants. Here, we demonstrate that PROTEOSTAT-labeled aggregates are not the sole cause of photoreceptor cell death promoted by the Y178C rhodopsin mutation in vivo, and there may be alternate aggregate forms contributing to cell death in these mice.","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"32"},"PeriodicalIF":6.1,"publicationDate":"2025-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11775123/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143058013","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Regulatory role of PPAR in colorectal cancer.

IF 6.1 2区生物学

Cell Death Discovery Pub Date : 2025-01-28 DOI: 10.1038/s41420-025-02313-2

Cong Wang, Tingcong Lv, Binghui Jin, Yang Li, Zhe Fan

引用次数: 0

Perilipin2-dependent lipid droplets accumulation promotes metastasis of oral squamous cell carcinoma via epithelial-mesenchymal transition.

IF 6.1 2区生物学

Cell Death Discovery Pub Date : 2025-01-28 DOI: 10.1038/s41420-025-02314-1

Jiayu Zhang, Jianmin Peng, Siyu Wang, Li Wang, Yutong Sun, Juan Xia, Bin Cheng, Qinchao Hu

{"title":"Perilipin2-dependent lipid droplets accumulation promotes metastasis of oral squamous cell carcinoma via epithelial-mesenchymal transition.","authors":"Jiayu Zhang, Jianmin Peng, Siyu Wang, Li Wang, Yutong Sun, Juan Xia, Bin Cheng, Qinchao Hu","doi":"10.1038/s41420-025-02314-1","DOIUrl":"10.1038/s41420-025-02314-1","url":null,"abstract":"Emerging evidence shows that lipid metabolic reprogramming plays a vital role in tumor metastasis. The effect and mechanism of fatty acids and lipid droplets (LDs), the core products of lipid metabolism, on the metastasis of oral squamous cell carcinoma (OSCC), need further exploration. In this study, the influence of palmitic acid (PA) and oleic acid (OA) on the migration and invasion ability of OSCC cells was determined by in vitro experiments. Genetic manipulation of PLIN2 was performed to explore its effect on the accumulation of LDs and OSCC metastasis. Possible mechanisms of these biological effects were clarified by detecting the levels of epithelial-mesenchymal transition (EMT) markers and phosphatidylinositol 3-kinase (PI3K) pathway proteins as well as conducting various bioinformatics analyses. The results indicated that PA/OA promoted the migration and invasion of OSCC cells and induced PLIN2-dependent LDs accumulation in vitro. Knockdown of PLIN2 inhibited the LDs accumulation and the migration and invasion of OSCC cells in vitro, while overexpression of PLIN2 enhanced those of OSCC cells in vitro and also promoted the metastasis of OSCC in vivo. Besides, PLIN2 up-regulation activated the PI3K pathway and subsequently enhanced EMT in OSCC cells in vitro. OSCC patients with higher PLIN2 expression possessed poorer prognosis and higher sensitivity to chemotherapy drugs (1S,3 R)-RSL3 and ML-210. In conclusion, PLIN2-dependent LDs accumulation could promote the metastasis of OSCC cells by regulating EMT. PLIN2 might be a potential therapeutic target for OSCC patients, especially those with obesity.","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"30"},"PeriodicalIF":6.1,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11775315/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143058037","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

SPHK1 enhances olaparib resistance in ovarian cancer through the NFκB/NRF2/ferroptosis pathway.

IF 6.1 2区生物学

Cell Death Discovery Pub Date : 2025-01-28 DOI: 10.1038/s41420-025-02309-y

Kai Teng, Hanlin Ma, Panpan Gai, Xuelian Zhao, Gonghua Qi

{"title":"SPHK1 enhances olaparib resistance in ovarian cancer through the NFκB/NRF2/ferroptosis pathway.","authors":"Kai Teng, Hanlin Ma, Panpan Gai, Xuelian Zhao, Gonghua Qi","doi":"10.1038/s41420-025-02309-y","DOIUrl":"10.1038/s41420-025-02309-y","url":null,"abstract":"PARPis resistance is a challenge in the treatment of ovarian cancer. To investigate the potential mechanism involved in olaparib resistance of ovarian cancer, high-throughput sequencing was performed on olaparib-resistant SKOV3 cell line named SK/Ola. SPHK1 was upregulated in SK/Ola cells and was related to the PFS and OS in ovarian cancer patients. However, the effect and mechanism of SPHK1 on olaparib sensitivity in ovarian cancer were obscure. In this study, we found that SPHK1 promoted olaparib resistance. While, SPHK1 knockdown and SPHK1 inhibitor (PF-543 hydrochloride, named PF-543 in this article) enhanced the effect of olaparib on ovarian cancer cells. In mechanism, SPHK1 activated the NF-κB pathway through promoting p-IκBα degradation. Moreover, SPHK1 inhibited, but PF-543 activated ferroptosis in OC cells. Further investigation revealed that SPHK1 activated NF-κB p65, which in turn transcriptionally regulated NRF2 to inhibit ferroptosis in OC cells. Functionally, NF-κB p65 attenuated the PF-543-induced ferroptosis, and this effect was rescued by ferroptosis inducer erastin and RSL3. We conclude that SPHK1 inhibition triggers ferroptosis by restricting NF-κB-activated NRF2 transcription, thereby enhancing olaparib sensitivity in ovarian cancer. In vivo experiments also confirmed that the SPHK1 inhibitor increased olaparib sensitivity. A combination of SPHK1 inhibitors and olaparib may provide a therapeutic strategy for ovarian cancer.","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"29"},"PeriodicalIF":6.1,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11775125/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143058062","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

PARP inhibition-associated heterochromatin confers increased DNA replication stress and vulnerability to ATR inhibition in SMARCA4-deficient cells.

IF 6.1 2区生物学

Cell Death Discovery Pub Date : 2025-01-28 DOI: 10.1038/s41420-025-02306-1

Kimiyoshi Yano, Megumi Kato, Syoju Endo, Taichi Igarashi, Ryoga Wada, Takashi Kohno, Astrid Zimmermann, Heike Dahmen, Frank T Zenke, Bunsyo Shiotani

{"title":"PARP inhibition-associated heterochromatin confers increased DNA replication stress and vulnerability to ATR inhibition in SMARCA4-deficient cells.","authors":"Kimiyoshi Yano, Megumi Kato, Syoju Endo, Taichi Igarashi, Ryoga Wada, Takashi Kohno, Astrid Zimmermann, Heike Dahmen, Frank T Zenke, Bunsyo Shiotani","doi":"10.1038/s41420-025-02306-1","DOIUrl":"10.1038/s41420-025-02306-1","url":null,"abstract":"DNA replication stress (RS), a prevalent feature of various malignancies, arises from both genetic mutations and genotoxic exposure. Elevated RS levels increase the vulnerability of cancer cells to ataxia telangiectasia and Rad3-related kinase inhibitors (ATRis). Here, we screened for DNA damage response inhibitors that enhance ATRi-induced cytotoxicity using SWI/SNF complex-deficient cells and identified a potent synergy between ATRi and poly(ADP-ribose) polymerase inhibitor (PARPi), particularly in SMARCA4-deficient cells. PARP inhibition triggers chromatin changes, namely elevated histone H3 at lysine 9 di-methylation (H3K9me2), a hallmark of facultative heterochromatin, increasing dependence on ATR activity for replication fork progression and cell survival. Interestingly, SMARCA4 deficient cells, intrinsically vulnerable to replication stress, exhibited exacerbated DNA damage upon combined ATRi and PARPi treatment in a Mre11- and Mus81-mediated manner. In vivo, combined treatment with intermittent ATRi and continuous PARPi showed greater inhibition of tumor growth than ATRi alone in SMARCA4-deficient lung adenocarcinoma xenograft models. These findings demonstrate that PARPi-induced heterochromatin amplifies RS and ATRi susceptibility, providing a potential rationale for therapeutic strategies targeting SMARCA4-deficient tumors.","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"31"},"PeriodicalIF":6.1,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11775187/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143058032","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0