Cell Death Discovery最新文献

Limiting serine availability during tumor progression promotes muscle wasting in cancer cachexia.

IF 6.1 2区生物学

Cell Death Discovery Pub Date : 2024-12-21 DOI: 10.1038/s41420-024-02271-1

Erica Pranzini, Livio Muccillo, Ilaria Nesi, Alice Santi, Caterina Mancini, Giulia Lori, Massimo Genovese, Tiziano Lottini, Giuseppina Comito, Anna Caselli, Annarosa Arcangeli, Lina Sabatino, Vittorio Colantuoni, Maria Letizia Taddei, Paolo Cirri, Paolo Paoli

{"title":"Limiting serine availability during tumor progression promotes muscle wasting in cancer cachexia.","authors":"Erica Pranzini, Livio Muccillo, Ilaria Nesi, Alice Santi, Caterina Mancini, Giulia Lori, Massimo Genovese, Tiziano Lottini, Giuseppina Comito, Anna Caselli, Annarosa Arcangeli, Lina Sabatino, Vittorio Colantuoni, Maria Letizia Taddei, Paolo Cirri, Paolo Paoli","doi":"10.1038/s41420-024-02271-1","DOIUrl":"https://doi.org/10.1038/s41420-024-02271-1","url":null,"abstract":"Cancer cachexia is a multifactorial syndrome characterized by a progressive loss of body weight occurring in about 80% of cancer patients, frequently representing the leading cause of death. Dietary intervention is emerging as a promising therapeutic strategy to counteract cancer-induced wasting. Serine is the second most-consumed amino acid (AA) by cancer cells and has emerged to be strictly necessary to preserve skeletal muscle structure and functionality. Here, we demonstrate that decreased serine availability during tumor progression promotes myotubes diameter reduction in vitro and induces muscle wasting in in vivo mice models. By investigating the metabolic crosstalk between colorectal cancer cells and muscle cells, we found that incubating myotubes with conditioned media from tumor cells relying on exogenous serine consumption triggers pronounced myotubes diameter reduction. Accordingly, culturing myotubes in a serine-free medium induces fibers width reduction and suppresses the activation of the AKT-mTORC1 pathway with consequent impairment in protein synthesis, increased protein degradation, and enhanced expression of the muscle atrophy-related genes Atrogin1 and MuRF1. In addition, serine-starved conditions affect myoblast differentiation and mitochondrial oxidative metabolism, finally inducing oxidative stress in myotubes. Consistently, serine dietary deprivation strongly strengthens cancer-associated weight loss and muscle atrophy in mice models. These findings uncover serine consumption by tumor cells as a previously undisclosed driver in cancer cachexia, opening new routes for possible therapeutic approaches.","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"10 1","pages":"510"},"PeriodicalIF":6.1,"publicationDate":"2024-12-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142871501","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

MEG8 as an antagonistic pleiotropic mechanism in breast cancer.

IF 6.1 2区生物学

Cell Death Discovery Pub Date : 2024-12-20 DOI: 10.1038/s41420-024-02272-0

Eva M Verdugo-Sivianes, Asunción Espinosa-Sánchez, Ildefonso Cases, Ana M Rojas, Daniel Otero-Albiol, Lourdes Romero, José Ramón Blanco, Amancio Carnero

{"title":"MEG8 as an antagonistic pleiotropic mechanism in breast cancer.","authors":"Eva M Verdugo-Sivianes, Asunción Espinosa-Sánchez, Ildefonso Cases, Ana M Rojas, Daniel Otero-Albiol, Lourdes Romero, José Ramón Blanco, Amancio Carnero","doi":"10.1038/s41420-024-02272-0","DOIUrl":"https://doi.org/10.1038/s41420-024-02272-0","url":null,"abstract":"Cellular senescence connects aging and cancer. Cellular senescence is a common program activated by cells in response to various types of stress. During this process, cells lose their proliferative capacity and undergo distinct morphological and metabolic changes. Senescence itself constitutes a tumor suppression mechanism and plays a significant role in organismal aging by promoting chronic inflammation. Additionally, age is one of the major risk factors for developing breast cancer. Therefore, while senescence can suppress tumor development early in life, it can also lead to an aging process that drives the development of age-related pathologies, suggesting an antagonistic pleiotropic effect. In this work, we identified Rian/MEG8 as a potential biomarker connecting aging and breast cancer for the first time. We found that Rian/MEG8 expression decreases with age; however, it is high in mice that age prematurely. We also observed decreased MEG8 expression in breast tumors compared to normal tissue. Furthermore, MEG8 overexpression reduced the proliferative and stemness properties of breast cancer cells both in vitro and in vivo by activating apoptosis. MEG8 could exemplify the antagonistic pleiotropic theory, where senescence is beneficial early in life as a tumor suppression mechanism due to increased MEG8, resulting in fewer breast tumors at an early age. Conversely, this effect could be detrimental later in life due to aging and cancer, when MEG8 is reduced and loses its tumor-suppressive role.","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"10 1","pages":"509"},"PeriodicalIF":6.1,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142871502","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Deptor protects against myocardial ischemia-reperfusion injury by regulating the mTOR signaling and autophagy.

IF 6.1 2区生物学

Cell Death Discovery Pub Date : 2024-12-19 DOI: 10.1038/s41420-024-02263-1

Qunjun Duan, Weijun Yang, Xian Zhu, Zhanzeng Feng, Jiangwei Song, Xiaobin Xu, Minjian Kong, Jiayan Mao, Jian Shen, Yuqin Deng, Rujia Tao, Hongfei Xu, Wei Chen, Weidong Li, Aiqiang Dong, Jie Han

{"title":"Deptor protects against myocardial ischemia-reperfusion injury by regulating the mTOR signaling and autophagy.","authors":"Qunjun Duan, Weijun Yang, Xian Zhu, Zhanzeng Feng, Jiangwei Song, Xiaobin Xu, Minjian Kong, Jiayan Mao, Jian Shen, Yuqin Deng, Rujia Tao, Hongfei Xu, Wei Chen, Weidong Li, Aiqiang Dong, Jie Han","doi":"10.1038/s41420-024-02263-1","DOIUrl":"https://doi.org/10.1038/s41420-024-02263-1","url":null,"abstract":"Deptor knockout mice were constructed by crossing Deptor Floxp3 mice with myh6 Cre mice, establishing a myocardial ischemia-reperfusion (I/R) model. Deptor knockout mice exhibited significantly increased myocardial infarction size and increased myocardial apoptosis in vivo. ELISA analysis indicated that the expression of CK-MB, LDH, and CtnT/I was significantly higher in the Deptor knockout mice. Deptor siRNA significantly reduced cell activity and increased myocardial apoptosis after I/R-induced in vitro. Deptor siRNA also significantly up-regulated the expression of p-mTOR, p-4EBP1, and p62, and down-regulated the expression of LC3 after I/R induction. Immunofluorescence indicated that LC3 dual fluorescence was weakened by Deptor knockout, and was enhanced after transfection with Deptor-overexpression plasmids. Treatment with OSI027, a co-inhibitor of mTORC1 and mTORC2, in either Deptor knockout mice or Deptor knockout H9C2 cells, resulted in a significant reduction in infarction size and apoptotic cardiomyocytes. ELISA analysis also showed that the expression of CK-MB, LDH, and CtnT/I were significantly down-regulated by treatment with OSI027. CCK-8 cell viability indicated that cell viability was enhanced, and the number of apoptotic cells was decreased in vitro following treatment with OSI027. These results revealed that OSI027 exerts a protective effect on myocardial ischemia/reperfusion injury in both an in vivo and in an in vitro model of I/R. These findings demonstrate that Deptor protects against I/R-induced myocardial injury by inhibiting the mTOR pathway and by increasing autophagy.","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"10 1","pages":"508"},"PeriodicalIF":6.1,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142863364","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

17β-estradiol alleviated ferroptotic neuroinflammation by suppressing ATF4 in mouse model of Parkinson's disease.

IF 6.1 2区生物学

Cell Death Discovery Pub Date : 2024-12-19 DOI: 10.1038/s41420-024-02273-z

Guoming Wang, Wenxin Zhuang, Yijun Zhou, Xu Wang, Zhenfeng Li, Chuanliang Liu, Wentong Li, Maotao He, E Lv

{"title":"17β-estradiol alleviated ferroptotic neuroinflammation by suppressing ATF4 in mouse model of Parkinson's disease.","authors":"Guoming Wang, Wenxin Zhuang, Yijun Zhou, Xu Wang, Zhenfeng Li, Chuanliang Liu, Wentong Li, Maotao He, E Lv","doi":"10.1038/s41420-024-02273-z","DOIUrl":"https://doi.org/10.1038/s41420-024-02273-z","url":null,"abstract":"Neuroinflammation induced by activation of microglial is a vital contributor to progression of Parkinson's disease (PD), emerging evidences suggested that ferroptosis played a pivotal role in microglial activation and subsequent dopaminergic neuron loss. Nevertheless, the fundamental pathogenesis of that ferroptosis contributes to PD is not yet sufficiently understood. Based on GEO dataset, ferroptosis related genes were found to be enriched in PD patients and MPTP mouse model of PD, among them, ATF4 was found to be dramatically differentially expressed. In our study, ectopic expression of ATF4 augmented MPP+-induced cytotoxic and activation of BV2 cells with upregulated intracellular L-ROS, TLR4 and pNF-κB. Ectopic ATF4 effectively promoted transformation of microglial into M1 pro-inflammatory phenotype. 17β-estradiol (E2) attenuated expression of ATF4 in BV2 cells, silence of ATF4 enhanced protective effect of E2 on MPP+-treated BV2 cells. In MPTP-induced PD mouse model, administration of E2 further abated expression of ATF4 and inhibited expressions of pro-inflammatory cytokines and activation of TLR4/NF-κB pathway. Overall, E2 effectively counteracted TLR4/NF-κB signaling pathway by restraining ATF4 and inhibited inflammatory response triggered by ferroptosis, ultimately exerted anti-PD effects.","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"10 1","pages":"507"},"PeriodicalIF":6.1,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142863363","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

USP39 regulates pyruvate handling in non-small cell lung cancer.

IF 6.1 2区生物学

Cell Death Discovery Pub Date : 2024-12-18 DOI: 10.1038/s41420-024-02264-0

Tina Becirovic, Boxi Zhang, Helin Vakifahmetoglu-Norberg, Vitaliy O Kaminskyy, Elena Kochetkova, Erik Norberg

{"title":"USP39 regulates pyruvate handling in non-small cell lung cancer.","authors":"Tina Becirovic, Boxi Zhang, Helin Vakifahmetoglu-Norberg, Vitaliy O Kaminskyy, Elena Kochetkova, Erik Norberg","doi":"10.1038/s41420-024-02264-0","DOIUrl":"https://doi.org/10.1038/s41420-024-02264-0","url":null,"abstract":"The ubiquitin-specific peptidase 39 (USP39) belongs to the USP family of cysteine proteases representing the largest group of human deubiquitinases (DUBs). While the oncogenic function of USP39 has been investigated in various cancer types, its roles in non-small cell lung cancer (NSCLC) remain largely unknown. Here, by applying a gene set enrichment analysis (GSEA) on lung adenocarcinoma tissues and metabolite set enrichment analysis (MSEA) on NSCLC cells depleted of USP39, we identified a previously unknown link between USP39 and the metabolism in NSCLC cells. Mechanistically, we uncovered a component of the pyruvate dehydrogenase (PDH) complex, pyruvate dehydrogenase E1 subunit alpha (PDHA), as a target of USP39. We further present that USP39 silencing caused an elevation in Lys63 ubiquitination on PDHA and a reduction in the PDH complex activity, the levels of TCA cycle intermediates, mitochondrial respiration, cell proliferation in vitro, and of tumor growth in vivo. Consistently, citrate supplementation restored mitochondrial respiration and cell growth in USP39-depleted cells. Our study elucidates and describes how USP39 regulates pyruvate metabolism through a deubiquitylation process that affects NSCLC tumor growth.","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"10 1","pages":"502"},"PeriodicalIF":6.1,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142853088","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Oleanolic acid combined with aspirin plays antitumor roles in colorectal cancer via the Akt/NFκB/IκBα/COX2 pathway.

IF 6.1 2区生物学

Cell Death Discovery Pub Date : 2024-12-18 DOI: 10.1038/s41420-024-02223-9

Yulv Zhou, Shengnan Lin, Xinzhu Zhong, Fang Huang, Jinxiang Huang, Luning Xu

{"title":"Oleanolic acid combined with aspirin plays antitumor roles in colorectal cancer via the Akt/NFκB/IκBα/COX2 pathway.","authors":"Yulv Zhou, Shengnan Lin, Xinzhu Zhong, Fang Huang, Jinxiang Huang, Luning Xu","doi":"10.1038/s41420-024-02223-9","DOIUrl":"https://doi.org/10.1038/s41420-024-02223-9","url":null,"abstract":"Among the common malignancies, colorectal cancer (CRC) is often resistant to chemotherapy because of drug resistance and severe toxicity. Currently, aspirin is one of the most promising CRC chemopreventive drugs, both for primary prevention and for reducing the chance of recurrence and metastasis following radical surgery in patients with early-stage CRC. Oleanolic acid is a potential antineoplastic drug that has an antagonistic effect on many kinds of tumors. Network pharmacology, molecular docking, and in vitro experiments were performed to investigate whether OA combined with aspirin can enhance the anticancer effects of aspirin. As indicated by the network pharmacology results, oleanolic acid and aspirin can regulate multiple signaling pathways through multiple target proteins, including NFκB1IκBαPTGS2MAPK3PIK3CA. A series of cellular experiments demonstrated for the first time that oleanolic acid synergistically enhances aspirin to inhibit the proliferation and invasion of HCT116 and HT29 cells and induce S-phase arrest by regulating Akt/NFκB/IκBα/COX2 signaling pathway, thus synergistically enhancing the ability of aspirin to promote apoptosis of colorectal cancer cells. This study provides a novel approach to the use of fresh medications for the treatment of colorectal cancer and offers a theoretical foundation for the potential creation of aspirin derivatives based on oleanolic acid.","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"10 1","pages":"504"},"PeriodicalIF":6.1,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142853065","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

USP21-EGFR signaling axis is functionally implicated in metastatic colorectal cancer.

IF 6.1 2区生物学

Cell Death Discovery Pub Date : 2024-12-18 DOI: 10.1038/s41420-024-02255-1

Ji Hye Shin, Mi-Jeong Kim, Ji Young Kim, Bongkum Choi, Yeeun Kang, Seo Hyun Kim, Ha-Jeong Lee, Dohee Kwon, Yong Beom Cho, Kyeong Kyu Kim, Eunyoung Chun, Ki-Young Lee

{"title":"USP21-EGFR signaling axis is functionally implicated in metastatic colorectal cancer.","authors":"Ji Hye Shin, Mi-Jeong Kim, Ji Young Kim, Bongkum Choi, Yeeun Kang, Seo Hyun Kim, Ha-Jeong Lee, Dohee Kwon, Yong Beom Cho, Kyeong Kyu Kim, Eunyoung Chun, Ki-Young Lee","doi":"10.1038/s41420-024-02255-1","DOIUrl":"https://doi.org/10.1038/s41420-024-02255-1","url":null,"abstract":"The emerging role of ubiquitin-specific peptidase 21 (USP21) in stabilizing Fra-1 (FOSL1) highlights its involvement in promoting colorectal cancer (CRC) metastasis. Additionally, a reciprocal link between EGFR signaling and Fra-1 activation has been identified, mediated through matrix metalloproteinases (MMPs). However, the functional implications of the USP21-EGFR signaling axis in metastatic CRC (mCRC) are not fully understood. To investigate the clinical correlation between USP21 and EGFR expression, RNA-Seq data from tumor tissues (n = 27) and matched normal tissues (n = 27) of 27 mCRC patients were analyzed. Functional studies were performed, including the use of CRISPR/Cas9 to generate USP21-knockout (USP21-KO) CRC cells, in vitro assays for cancer progression and tumor formation, in vivo xenograft assays in NSG mice. Additionally, the therapeutic effect of the USP21 inhibitor, BAY-805, was evaluated. We found that elevated levels of USP21 and EGFR expression in mCRC patients were associated with poorer survival outcomes. Mechanistically, USP21 was found to enhance EGFR stability by deubiquitinating EGFR, leading to reduced EGFR degradation. USP21-KO colon cancer cells exhibited significantly reduced proliferation, migration, colony formation, and 3D tumor spheroid formation in response to EGF. Furthermore, the tumorigenic activity in vivo was markedly diminished in NSG mice xenografted with USP21-KO colon cancer cells. Importantly, BAY-805 demonstrated a notable inhibitory effect on the formation of 3D tumor spheroids in colorectal cancer cells stimulated with EGF. These findings suggest that USP21 could be a valuable therapeutic target and predictive biomarker for managing mCRC driven by EGF.","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"10 1","pages":"492"},"PeriodicalIF":6.1,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142853085","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

SMURF1 and SMURF2 directly target GLI1 for ubiquitination and proteasome-dependent degradation.

IF 6.1 2区生物学

Cell Death Discovery Pub Date : 2024-12-18 DOI: 10.1038/s41420-024-02260-4

Fabio Bordin, Gloria Terriaca, Adriano Apostolico, Annamaria Di Fiore, Faranak Taj Mir, Sara Bellardinelli, Francesca Bufalieri, Rosa Bordone, Francesca Bellardinilli, Giuseppe Giannini, Gianluca Canettieri, Lucia Di Marcotullio, Elisabetta Ferretti, Marta Moretti, Enrico De Smaele

{"title":"SMURF1 and SMURF2 directly target GLI1 for ubiquitination and proteasome-dependent degradation.","authors":"Fabio Bordin, Gloria Terriaca, Adriano Apostolico, Annamaria Di Fiore, Faranak Taj Mir, Sara Bellardinelli, Francesca Bufalieri, Rosa Bordone, Francesca Bellardinilli, Giuseppe Giannini, Gianluca Canettieri, Lucia Di Marcotullio, Elisabetta Ferretti, Marta Moretti, Enrico De Smaele","doi":"10.1038/s41420-024-02260-4","DOIUrl":"https://doi.org/10.1038/s41420-024-02260-4","url":null,"abstract":"The transcription factor GLI1 is the main and final effector of the Hedgehog signaling pathway, which is involved in embryonic development, cell proliferation and stemness. Whether activated through canonical or non-canonical mechanisms, GLI1 aberrant activity is associated with Hedgehog-dependent cancers, including medulloblastoma, as well as other tumoral contexts. Notwithstanding a growing body of evidence, which have highlighted the potential role of post translational modifications of GLI1, the complex mechanisms modulating GLI1 stability and activity have not been fully elucidated. Here, we present a novel role played by SMURF1 and SMURF2 in the suppression of the Hedgehog/GLI signaling pathway through a direct targeting of GLI1. Indeed, the two SMURFs can interact with GLI1, exploiting the proline rich regions present on GLI1 protein, and trigger its polyubiquitination and proteasomal degradation, leading to a suppression of the Hedgehog pathway activity and a reduction of Hh-dependent tumor cell proliferation. Overall, this study adds new relevance to a tumor suppressive role of SMURFs on the Hedgehog pathway and confers upon them the status of potential therapeutic tools, either in canonical or non-canonical Hedgehog pathway aberrant activation.","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"10 1","pages":"498"},"PeriodicalIF":6.1,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142853107","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

TFAP2A drives non-small cell lung cancer (NSCLC) progression and resistance to targeted therapy by facilitating the ESR2-mediated MAPK pathway.

IF 6.1 2区生物学

Cell Death Discovery Pub Date : 2024-12-18 DOI: 10.1038/s41420-024-02251-5

Ding-Guo Wang, Jian Gao, Jing Wang, Kun-Chao Li, Zhi-Bo Wu, Zhong-Min Liao, Yong-Bing Wu

{"title":"TFAP2A drives non-small cell lung cancer (NSCLC) progression and resistance to targeted therapy by facilitating the ESR2-mediated MAPK pathway.","authors":"Ding-Guo Wang, Jian Gao, Jing Wang, Kun-Chao Li, Zhi-Bo Wu, Zhong-Min Liao, Yong-Bing Wu","doi":"10.1038/s41420-024-02251-5","DOIUrl":"https://doi.org/10.1038/s41420-024-02251-5","url":null,"abstract":"Cancer is among the leading causes of death related diseases worldwide, and lung cancer has the highest mortality rate in the world. Transcription factors (TFs) constitute a class of structurally and functionally intricate proteins. Aberrant expression or functional deficiencies of transcription factors may give rise to abnormal gene expression, contributing to various diseases, including tumours. In this study, we propose to elucidate the potential role and mechanism of TFAP2A in NSCLC. We found that TFAP2A levels were significantly greater in tumour tissues than para-tumour tissues, and high expression of TFAP2A was associated with poor prognosis in NSCLC patients. Additionally, TFAP2A overexpression promoted NSCLC progression both in vivo and in vitro. Mechanistically, ESR2 is a potential target regulated by TFAP2A and that TFAP2A can bind to the promoter region of ESR2. Furthermore, the overexpression of both TFAP2A and ESR2 in NSCLC cells was associated with the overactivation of MAPK signalling, and the combination of PHTPP and osimertinib had a synergistic effect on suppressing tumour growth.","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"10 1","pages":"491"},"PeriodicalIF":6.1,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142853109","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Cardiocutaneous syndrome is caused by aggregation of iASPP mutants.

IF 6.1 2区生物学

Cell Death Discovery Pub Date : 2024-12-18 DOI: 10.1038/s41420-024-02265-z

Rebecca Lotz, Christian Osterburg, Birgit Schäfer, Xin Lu, Volker Dötsch

{"title":"Cardiocutaneous syndrome is caused by aggregation of iASPP mutants.","authors":"Rebecca Lotz, Christian Osterburg, Birgit Schäfer, Xin Lu, Volker Dötsch","doi":"10.1038/s41420-024-02265-z","DOIUrl":"https://doi.org/10.1038/s41420-024-02265-z","url":null,"abstract":"The ASPP (apoptosis-stimulating protein of p53) family of proteins is involved in many cellular interactions and is starting to emerge as a major scaffolding hub for numerous proteins involved in cancer biology, inflammation and cellular integrity. It consists of the three members ASPP1, ASPP2 and iASPP which are best known for modulating the apoptotic function of p53, thereby directing cell fate decision. Germline mutations in iASPP have been shown to cause cardiocutaneous syndromes, a combination of heart and skin defects usually leading to death before the age of five. Mutations in iASPP causing these syndromes do not cluster in hot spots but are distributed throughout the protein. To understand the molecular mechanism(s) of how mutations in iASPP cause the development of cardiocutaneous syndromes we analysed the stability and solubility of iASPP mutants, characterized their interaction with chaperones and investigated their influence on NF-ĸB activity. Here we show that three different mechanisms are responsible for loss of function of iASPP: loss of the complete C-terminal domain, mutations resulting in increased auto-inhibition and aggregation due to destabilization of the C-terminal domain. In contrast to these germline mutations causing cardiocutaneous syndromes, missense mutations found in cancer do not result in aggregation.","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"10 1","pages":"497"},"PeriodicalIF":6.1,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142853004","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0