Pub Date : 2024-08-22DOI: 10.1038/s41419-024-07009-6
Mei Huang, Xiaotong Zhu, Chen Wang, Liying He, Lei Li, Haopeng Wang, Gaofeng Fan, Yu Wang
PARP1 is crucial in DNA damage repair, chromatin remodeling, and transcriptional regulation. The principle of synthetic lethality has effectively guided the application of PARP inhibitors in treating tumors carrying BRCA1/2 mutations. Meanwhile, PARP inhibitors have exhibited efficacy in BRCA-proficient patients, further highlighting the necessity for a deeper understanding of PARP1 function and its inhibition in cancer therapy. Here, we unveil PIN2/TRF1-interacting telomerase inhibitor 1 (PINX1) as an uncharacterized PARP1-interacting protein that synergizes with PARP inhibitors upon its depletion across various cancer cell lines. Loss of PINX1 compromises DNA damage repair capacity upon etoposide treatment. The vulnerability of PINX1-deficient cells to etoposide and PARP inhibitors could be effectively restored by introducing either a full-length or a mutant form of PINX1 lacking telomerase inhibitory activity. Mechanistically, PINX1 is recruited to DNA lesions through binding to the ZnF3-BRCT domain of PARP1, facilitating the downstream recruitment of the DNA repair factor XRCC1. In the absence of DNA damage, PINX1 constitutively binds to PARP1, promoting PARP1-chromatin association and transcription of specific DNA damage repair proteins, including XRCC1, and transcriptional regulators, including GLIS3. Collectively, our findings identify PINX1 as a multifaceted partner of PARP1, crucial for safeguarding cells against genotoxic stress and emerging as a potential candidate for targeted tumor therapy.
PARP1 在 DNA 损伤修复、染色质重塑和转录调控中至关重要。合成致死原则有效地指导了 PARP 抑制剂在治疗携带 BRCA1/2 基因突变的肿瘤中的应用。同时,PARP 抑制剂在 BRCA 基因缺陷患者中也显示出了疗效,这进一步凸显了深入了解 PARP1 功能及其在癌症治疗中的抑制作用的必要性。在这里,我们揭示了 PIN2/TRF1-interacting telomerase inhibitor 1(PINX1),它是一种未定性的 PARP1-interacting蛋白,在各种癌细胞系中,当它被去除了时,会与 PARP 抑制剂产生协同作用。PINX1 的缺失会损害依托泊苷治疗时的 DNA 损伤修复能力。通过引入全长或缺乏端粒酶抑制活性的突变形式的PINX1,可有效恢复PINX1缺陷细胞对依托泊苷和PARP抑制剂的脆弱性。从机理上讲,PINX1通过与PARP1的ZnF3-BRCT结构域结合被招募到DNA损伤处,从而促进DNA修复因子XRCC1的下游招募。在没有 DNA 损伤的情况下,PINX1 与 PARP1 构成性结合,促进 PARP1 与染色质的结合,并促进特定 DNA 损伤修复蛋白(包括 XRCC1)和转录调节因子(包括 GLIS3)的转录。总之,我们的研究结果表明,PINX1 是 PARP1 的多方面伙伴,对保护细胞免受基因毒性应激至关重要,是肿瘤靶向治疗的潜在候选者。
{"title":"PINX1 loss confers susceptibility to PARP inhibition in pan-cancer cells.","authors":"Mei Huang, Xiaotong Zhu, Chen Wang, Liying He, Lei Li, Haopeng Wang, Gaofeng Fan, Yu Wang","doi":"10.1038/s41419-024-07009-6","DOIUrl":"10.1038/s41419-024-07009-6","url":null,"abstract":"<p><p>PARP1 is crucial in DNA damage repair, chromatin remodeling, and transcriptional regulation. The principle of synthetic lethality has effectively guided the application of PARP inhibitors in treating tumors carrying BRCA1/2 mutations. Meanwhile, PARP inhibitors have exhibited efficacy in BRCA-proficient patients, further highlighting the necessity for a deeper understanding of PARP1 function and its inhibition in cancer therapy. Here, we unveil PIN2/TRF1-interacting telomerase inhibitor 1 (PINX1) as an uncharacterized PARP1-interacting protein that synergizes with PARP inhibitors upon its depletion across various cancer cell lines. Loss of PINX1 compromises DNA damage repair capacity upon etoposide treatment. The vulnerability of PINX1-deficient cells to etoposide and PARP inhibitors could be effectively restored by introducing either a full-length or a mutant form of PINX1 lacking telomerase inhibitory activity. Mechanistically, PINX1 is recruited to DNA lesions through binding to the ZnF3-BRCT domain of PARP1, facilitating the downstream recruitment of the DNA repair factor XRCC1. In the absence of DNA damage, PINX1 constitutively binds to PARP1, promoting PARP1-chromatin association and transcription of specific DNA damage repair proteins, including XRCC1, and transcriptional regulators, including GLIS3. Collectively, our findings identify PINX1 as a multifaceted partner of PARP1, crucial for safeguarding cells against genotoxic stress and emerging as a potential candidate for targeted tumor therapy.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":null,"pages":null},"PeriodicalIF":8.1,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11341912/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142035344","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Diffuse large B-cell lymphoma (DLBCL), an invasive lymphoma with substantial heterogeneity, can be mainly categorised into germinal centre B-cell-like (GCB) and non-GCB subtypes. DLBCL cells are highly susceptible to ferroptosis, which offers an effective avenue for treating recurrent and refractory DLBCL. Moreover, various heat shock proteins are involved in regulating the sensitivity of tumour cells to ferroptosis. Among these proteins, tailless complex polypeptide 1 (TCP1), a subunit of chaperonin-containing T-complex protein-1 (CCT), plays a role in tumour proliferation and survival. Therefore, we explored the role of TCP1 in different DLBCL subtypes, the sensitivity of GCB and non-GCB subtypes to the ferroptosis inducer RAS-selective lethal small molecule 3 (RSL3), and the underlying molecular mechanism. In GCB cells, TCP1 promoted RSL3-induced ferroptosis. Notably, TCP1 could bind with acyl-CoA synthetase long-chain family member 4 (ACSL4), a key enzyme regulating lipid composition and facilitating ferroptosis, to reduce its ubiquitination and degradation. This interaction activated the ACSL4/LPCAT3 signalling pathway and promoted ferroptosis in the GCB subtype. However, in the non-GCB subtype, TCP1 did not act as a positive regulator but served as a predictor of an unfavourable prognosis in patients with non-GCB. In conclusion, our results suggest that in DLBCL, high TCP1 expression enhances the sensitivity of GCB tumour cells to ferroptosis and serves as a marker of poor prognosis in patients with non-GCB DLBCL.
{"title":"TCP1 expression alters the ferroptosis sensitivity of diffuse large B-cell lymphoma subtypes by stabilising ACSL4 and influences patient prognosis.","authors":"Shuxia Zhang, Jin Wang, Guanxiang Huang, Xueting Xiao, Shujuan Xu, Ping Weng, Yiting Wang, Huiyun Tian, Huifang Huang, Yuanzhong Chen","doi":"10.1038/s41419-024-07001-0","DOIUrl":"10.1038/s41419-024-07001-0","url":null,"abstract":"<p><p>Diffuse large B-cell lymphoma (DLBCL), an invasive lymphoma with substantial heterogeneity, can be mainly categorised into germinal centre B-cell-like (GCB) and non-GCB subtypes. DLBCL cells are highly susceptible to ferroptosis, which offers an effective avenue for treating recurrent and refractory DLBCL. Moreover, various heat shock proteins are involved in regulating the sensitivity of tumour cells to ferroptosis. Among these proteins, tailless complex polypeptide 1 (TCP1), a subunit of chaperonin-containing T-complex protein-1 (CCT), plays a role in tumour proliferation and survival. Therefore, we explored the role of TCP1 in different DLBCL subtypes, the sensitivity of GCB and non-GCB subtypes to the ferroptosis inducer RAS-selective lethal small molecule 3 (RSL3), and the underlying molecular mechanism. In GCB cells, TCP1 promoted RSL3-induced ferroptosis. Notably, TCP1 could bind with acyl-CoA synthetase long-chain family member 4 (ACSL4), a key enzyme regulating lipid composition and facilitating ferroptosis, to reduce its ubiquitination and degradation. This interaction activated the ACSL4/LPCAT3 signalling pathway and promoted ferroptosis in the GCB subtype. However, in the non-GCB subtype, TCP1 did not act as a positive regulator but served as a predictor of an unfavourable prognosis in patients with non-GCB. In conclusion, our results suggest that in DLBCL, high TCP1 expression enhances the sensitivity of GCB tumour cells to ferroptosis and serves as a marker of poor prognosis in patients with non-GCB DLBCL.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":null,"pages":null},"PeriodicalIF":8.1,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11341815/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142035345","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-21DOI: 10.1038/s41419-024-06990-2
Shaoxian Chen, Guiping Huang, Juli Liu
Monkeypox virus (MPV) is known to inflict injuries and, in some cases, lead to fatalities in humans. However, the underlying mechanisms responsible for its pathogenicity remain poorly understood. We investigated functions of MPV core proteins, H3L, A35R, A29L, and I1L, and discovered that H3L induced transcriptional perturbations and injuries. We substantiated that H3L upregulated IL1A expression. IL1A, in consequence, caused cellular injuries, and this detrimental effect was mitigated when countered with IL1A blockage. We also observed that H3L significantly perturbed the transcriptions of genes in cardiac system. Mechanistically, H3L occupied the promoters of genes governing cellular injury, leading to alterations in the binding patterns of H3K27me3 and H3K4me3 histone marks, ultimately resulting in expression perturbations. In vivo and in vitro models confirmed that H3L induced transcriptional disturbances and cardiac dysfunction, which were ameliorated when IL1A was blocked or repressed. Our study provides valuable insights into comprehensive understanding of MPV pathogenicity, highlights the significant roles of H3L in inducing injuries, and potentially paves the way for the development of therapeutic strategies targeting IL1A.
{"title":"Monkeypox virus protein H3L induces injuries in human and mouse.","authors":"Shaoxian Chen, Guiping Huang, Juli Liu","doi":"10.1038/s41419-024-06990-2","DOIUrl":"10.1038/s41419-024-06990-2","url":null,"abstract":"<p><p>Monkeypox virus (MPV) is known to inflict injuries and, in some cases, lead to fatalities in humans. However, the underlying mechanisms responsible for its pathogenicity remain poorly understood. We investigated functions of MPV core proteins, H3L, A35R, A29L, and I1L, and discovered that H3L induced transcriptional perturbations and injuries. We substantiated that H3L upregulated IL1A expression. IL1A, in consequence, caused cellular injuries, and this detrimental effect was mitigated when countered with IL1A blockage. We also observed that H3L significantly perturbed the transcriptions of genes in cardiac system. Mechanistically, H3L occupied the promoters of genes governing cellular injury, leading to alterations in the binding patterns of H3K27me3 and H3K4me3 histone marks, ultimately resulting in expression perturbations. In vivo and in vitro models confirmed that H3L induced transcriptional disturbances and cardiac dysfunction, which were ameliorated when IL1A was blocked or repressed. Our study provides valuable insights into comprehensive understanding of MPV pathogenicity, highlights the significant roles of H3L in inducing injuries, and potentially paves the way for the development of therapeutic strategies targeting IL1A.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":null,"pages":null},"PeriodicalIF":8.1,"publicationDate":"2024-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11339448/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142016447","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Recently, various cancer types have been identified to express a distinct subset of Interferon-stimulated genes (ISGs) that mediate therapy resistance. The mechanism through which cancer cells maintain prolonged Interferon stimulation effects to coordinate resistance remains unclear. Our research demonstrated that aberrant upregulation of TAGLN2 is associated with gastric cancer progression, and inhibiting its expression renders gastric cancer cells more susceptible to chemotherapy and radiation. We uncovered a novel role for TAGLN2 in the upregulation of resistance signature ISGs by enhancing YBX1-associated ssDNA aggregation and cGAS-STING pathway activation. TAGLN2 modulates YBX1 by recruiting c-Myc and SOX9 to YBX1 promoter region and directly interacting with AKT-YBX1, thereby enhancing YBX1 phosphorylation and nuclear translocation. Significantly, targeted downregulation of key proteins, inhibition of the TAGLN2-YBX1-AKT interaction (using Fisetin or MK2206) or disruption of the cGAS-STING pathway substantially reduced ssDNA accumulation, subsequent ISGs upregulation, and therapy resistance. The combination of Cisplatin with MK2206 displayed a synergistic effect in the higher TAGLN2-expressing xenograft tumors. Clinical analysis indicated that a derived nine-gene set effectively predicts therapeutic sensitivity and long-term prognosis in gastric cancer patients. These findings suggest that TAGLN2, YBX1 and induced ISGs are novel predictive markers for clinical outcomes, and targeting this axis is an attractive therapeutic sensitization strategy.
{"title":"TAGLN2 induces resistance signature ISGs by activating AKT-YBX1 signal with dual pathways and mediates the IFN-related DNA damage resistance in gastric cancer.","authors":"Huiqin Zhuo, Jingjing Hou, Zhijun Hong, Shuqi Yu, Huifang Peng, Lihua Zhang, Wen Xie, Xuehui Hong","doi":"10.1038/s41419-024-07000-1","DOIUrl":"10.1038/s41419-024-07000-1","url":null,"abstract":"<p><p>Recently, various cancer types have been identified to express a distinct subset of Interferon-stimulated genes (ISGs) that mediate therapy resistance. The mechanism through which cancer cells maintain prolonged Interferon stimulation effects to coordinate resistance remains unclear. Our research demonstrated that aberrant upregulation of TAGLN2 is associated with gastric cancer progression, and inhibiting its expression renders gastric cancer cells more susceptible to chemotherapy and radiation. We uncovered a novel role for TAGLN2 in the upregulation of resistance signature ISGs by enhancing YBX1-associated ssDNA aggregation and cGAS-STING pathway activation. TAGLN2 modulates YBX1 by recruiting c-Myc and SOX9 to YBX1 promoter region and directly interacting with AKT-YBX1, thereby enhancing YBX1 phosphorylation and nuclear translocation. Significantly, targeted downregulation of key proteins, inhibition of the TAGLN2-YBX1-AKT interaction (using Fisetin or MK2206) or disruption of the cGAS-STING pathway substantially reduced ssDNA accumulation, subsequent ISGs upregulation, and therapy resistance. The combination of Cisplatin with MK2206 displayed a synergistic effect in the higher TAGLN2-expressing xenograft tumors. Clinical analysis indicated that a derived nine-gene set effectively predicts therapeutic sensitivity and long-term prognosis in gastric cancer patients. These findings suggest that TAGLN2, YBX1 and induced ISGs are novel predictive markers for clinical outcomes, and targeting this axis is an attractive therapeutic sensitization strategy.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":null,"pages":null},"PeriodicalIF":8.1,"publicationDate":"2024-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11339399/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142016449","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-21DOI: 10.1038/s41419-024-06989-9
ShiHui Wang, JunLei Wang, Cui Liu, Lei Yang, XuanQian Tan, ShiYang Chen, Yun Xue, HongBin Ji, GaoXiang Ge, JianFeng Chen
Intercellular cell adhesion molecule-1 (ICAM-1) is frequently overexpressed in non-small cell lung cancer (NSCLC) and associated with poor prognosis. However, the mechanism underlying the negative effects of neoplastic ICAM-1 remains obscure. Herein, we demonstrate that the survival of NSCLC cells but not normal human bronchial epithelial cells requires an anti-apoptosis signal triggered by fibrinogen γ chain (FGG)-ICAM-1 interaction. ICAM-1-FGG ligation preserves the tyrosine phosphorylation of ICAM-1 cytoplasmic domain and its association with SHP-2, and subsequently promotes Akt and ERK1/2 activation but suppresses JNK and p38 activation. Abolishing ICAM-1-FGG interaction induces NSCLC cell death by activating caspase-9/3 and significantly inhibits tumor development in a mouse xenograft model. Finally, we developed a monoclonal antibody against ICAM-1-FGG binding motif, which blocks ICAM-1‒FGG interaction and effectively suppresses NSCLC cell survival in vitro and tumor growth in vivo. Thus, suppressing ICAM-1-FGG axis provides a potential strategy for NSCLC targeted therapy.
{"title":"Neoplastic ICAM-1 protects lung carcinoma from apoptosis through ligation of fibrinogen.","authors":"ShiHui Wang, JunLei Wang, Cui Liu, Lei Yang, XuanQian Tan, ShiYang Chen, Yun Xue, HongBin Ji, GaoXiang Ge, JianFeng Chen","doi":"10.1038/s41419-024-06989-9","DOIUrl":"10.1038/s41419-024-06989-9","url":null,"abstract":"<p><p>Intercellular cell adhesion molecule-1 (ICAM-1) is frequently overexpressed in non-small cell lung cancer (NSCLC) and associated with poor prognosis. However, the mechanism underlying the negative effects of neoplastic ICAM-1 remains obscure. Herein, we demonstrate that the survival of NSCLC cells but not normal human bronchial epithelial cells requires an anti-apoptosis signal triggered by fibrinogen γ chain (FGG)-ICAM-1 interaction. ICAM-1-FGG ligation preserves the tyrosine phosphorylation of ICAM-1 cytoplasmic domain and its association with SHP-2, and subsequently promotes Akt and ERK1/2 activation but suppresses JNK and p38 activation. Abolishing ICAM-1-FGG interaction induces NSCLC cell death by activating caspase-9/3 and significantly inhibits tumor development in a mouse xenograft model. Finally, we developed a monoclonal antibody against ICAM-1-FGG binding motif, which blocks ICAM-1‒FGG interaction and effectively suppresses NSCLC cell survival in vitro and tumor growth in vivo. Thus, suppressing ICAM-1-FGG axis provides a potential strategy for NSCLC targeted therapy.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":null,"pages":null},"PeriodicalIF":8.1,"publicationDate":"2024-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11339363/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142016448","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Lymphocyte decline, particularly the depletion of NK cells, is a prominent feature of immunosuppression following severe tissue injury, heightening the susceptibility of severe trauma patients to life-threatening infections. Previous research indicates that the reduction in the number of NK cells is closely associated with the process of cell death. Nonetheless, the precise mechanism of NK cell death remains unknown. Here, we discovered that following severe traumatic injury, NK cells undergo several cell death pathways, dominated by apoptosis and pyroptosis with coexistence of necrotic cell death, immunogenic cell death, ferroptosis, and autophagy. These NK cells with different paradigms of death have diverse cytokine expression profiles and diverse interactions with other immune cells. Further exploration revealed that hypoxia was strongly associated with this diverse paradigm of NK cell death. Detailed investigation of paradigms of cell death may help to enhance comprehension of lymphopenia post-severe trauma, to develop new strategy in preventing immunosuppression, and then to improve outcome for severe trauma population.
淋巴细胞的减少,尤其是 NK 细胞的耗竭,是严重组织损伤后免疫抑制的一个突出特征,使严重创伤患者更容易受到危及生命的感染。以往的研究表明,NK 细胞数量的减少与细胞死亡过程密切相关。然而,NK细胞死亡的确切机制仍然未知。在这里,我们发现严重创伤后,NK 细胞会经历多种细胞死亡途径,其中以细胞凋亡和热凋亡为主,坏死细胞死亡、免疫原性细胞死亡、铁凋亡和自噬并存。这些具有不同死亡模式的 NK 细胞具有不同的细胞因子表达谱以及与其他免疫细胞的不同相互作用。进一步的研究发现,缺氧与 NK 细胞的不同死亡模式密切相关。对细胞死亡模式的详细研究可能有助于加深对严重创伤后淋巴细胞减少症的理解,制定预防免疫抑制的新策略,进而改善严重创伤人群的预后。
{"title":"The different paradigms of NK cell death in patients with severe trauma.","authors":"Te-Ding Chang, Deng Chen, Jia-Liu Luo, Yu-Man Wang, Cong Zhang, Shun-Yao Chen, Zhi-Qiang Lin, Pei-Dong Zhang, Ting-Xuan Tang, Hui Li, Li-Ming Dong, Ning Wu, Zhao-Hui Tang","doi":"10.1038/s41419-024-06992-0","DOIUrl":"10.1038/s41419-024-06992-0","url":null,"abstract":"<p><p>Lymphocyte decline, particularly the depletion of NK cells, is a prominent feature of immunosuppression following severe tissue injury, heightening the susceptibility of severe trauma patients to life-threatening infections. Previous research indicates that the reduction in the number of NK cells is closely associated with the process of cell death. Nonetheless, the precise mechanism of NK cell death remains unknown. Here, we discovered that following severe traumatic injury, NK cells undergo several cell death pathways, dominated by apoptosis and pyroptosis with coexistence of necrotic cell death, immunogenic cell death, ferroptosis, and autophagy. These NK cells with different paradigms of death have diverse cytokine expression profiles and diverse interactions with other immune cells. Further exploration revealed that hypoxia was strongly associated with this diverse paradigm of NK cell death. Detailed investigation of paradigms of cell death may help to enhance comprehension of lymphopenia post-severe trauma, to develop new strategy in preventing immunosuppression, and then to improve outcome for severe trauma population.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":null,"pages":null},"PeriodicalIF":8.1,"publicationDate":"2024-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11339281/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142016450","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Natural killer/T cell lymphoma (NKTCL) exhibits highly aggressive clinical behavior, and the outcomes for relapsed/refractory patients are still poor. Recently, the mechanism underlying the effect of Epstein-Barr virus (EBV) infection, which has not been fully defined in NKTCL, has attracted great attention. We explored how LMP1 promoted aerobic glycolysis via metabolic sequencing combined with mRNA sequencing and immunoprecipitation coupled to mass spectrometry. Experimental assays were used to determine the effects of LMP1 and its downstream pathway on the function and glucose metabolism of NKTCL cells. The correlations between LMP1 expression in patients and their clinical features, treatment response, and prognosis were analyzed. Results show that LMP1 enhances NKTCL cell proliferation in vitro and in vivo, inhibits apoptosis, and decreases gemcitabine sensitivity. In addition, LMP1 also enhances aerobic glycolysis in NKTCL cells, as indicated by increases in glucose uptake, lactate production, and extracellular acidification rate. Clinically, LMP1 expression is correlated with risk stratification, treatment response, and prognosis, and higher LMP1 expression indicates greater SUVmax for NKTCL patients. Mechanistically, LMP1 competitively binds to TRAF3 to promote cell proliferation and aerobic glycolysis by regulating the noncanonical NF-κB pathway. The application of an NF-κB pathway inhibitor or reactivation of the NF-κB pathway affects aerobic glycolysis and the biological function of NKTCL cells. In summary, this study is the first to describe and define in detail how LMP1 affects glucose metabolism in NKTCL and might provide a novel perspective for further treatment.
{"title":"LMP1 enhances aerobic glycolysis in natural killer/T cell lymphoma.","authors":"Wenting Song, Yuyang Gao, Jiazhuo Wu, Hongwen Li, Zhuangzhuang Shi, Chen Gong, Zihe Zhang, Zhaoming Li, Mingzhi Zhang","doi":"10.1038/s41419-024-06999-7","DOIUrl":"10.1038/s41419-024-06999-7","url":null,"abstract":"<p><p>Natural killer/T cell lymphoma (NKTCL) exhibits highly aggressive clinical behavior, and the outcomes for relapsed/refractory patients are still poor. Recently, the mechanism underlying the effect of Epstein-Barr virus (EBV) infection, which has not been fully defined in NKTCL, has attracted great attention. We explored how LMP1 promoted aerobic glycolysis via metabolic sequencing combined with mRNA sequencing and immunoprecipitation coupled to mass spectrometry. Experimental assays were used to determine the effects of LMP1 and its downstream pathway on the function and glucose metabolism of NKTCL cells. The correlations between LMP1 expression in patients and their clinical features, treatment response, and prognosis were analyzed. Results show that LMP1 enhances NKTCL cell proliferation in vitro and in vivo, inhibits apoptosis, and decreases gemcitabine sensitivity. In addition, LMP1 also enhances aerobic glycolysis in NKTCL cells, as indicated by increases in glucose uptake, lactate production, and extracellular acidification rate. Clinically, LMP1 expression is correlated with risk stratification, treatment response, and prognosis, and higher LMP1 expression indicates greater SUVmax for NKTCL patients. Mechanistically, LMP1 competitively binds to TRAF3 to promote cell proliferation and aerobic glycolysis by regulating the noncanonical NF-κB pathway. The application of an NF-κB pathway inhibitor or reactivation of the NF-κB pathway affects aerobic glycolysis and the biological function of NKTCL cells. In summary, this study is the first to describe and define in detail how LMP1 affects glucose metabolism in NKTCL and might provide a novel perspective for further treatment.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":null,"pages":null},"PeriodicalIF":8.1,"publicationDate":"2024-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11335758/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142008299","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-20DOI: 10.1038/s41419-024-06987-x
Valeria Canu, Sebastiano Vaccarella, Andrea Sacconi, Claudio Pulito, Frauke Goeman, Matteo Pallocca, Daniela Rutigliano, Sima Lev, Sabrina Strano, Giovanni Blandino
Triple negative breast cancer (TNBC) is an aggressive disease which currently has no effective therapeutic targets and prominent biomarkers. The Sperm Associated antigen 5 (SPAG5) is a mitotic spindle associated protein with oncogenic function in several human cancers. In TNBC, increased SPAG5 expression has been associated with tumor progression, chemoresistance, relapse, and poor clinical outcome. Here we show that high SPAG5 expression in TNBC is regulated by coordinated activity of YAP, mutant p53 and MYC. Depletion of YAP or mutant p53 proteins reduced SPAG5 expression and the recruitment of MYC onto SPAG5 promoter. Targeting of MYC also reduced SPAG5 expression and concomitantly tumorigenicity of TNBC cells. These effects of MYC targeting were synergized with cytotoxic chemotherapy and markedly reduced TNBC oncogenicity in SPAG5-expression dependent manner. These results suggest that mutant p53-MYC-SPAG5 expression can be considered as bona fide predictors of patient's outcome, and reliable biomarkers for effective anticancer therapies.
{"title":"Targeting of mutant-p53 and MYC as a novel strategy to inhibit oncogenic SPAG5 activity in triple negative breast cancer.","authors":"Valeria Canu, Sebastiano Vaccarella, Andrea Sacconi, Claudio Pulito, Frauke Goeman, Matteo Pallocca, Daniela Rutigliano, Sima Lev, Sabrina Strano, Giovanni Blandino","doi":"10.1038/s41419-024-06987-x","DOIUrl":"10.1038/s41419-024-06987-x","url":null,"abstract":"<p><p>Triple negative breast cancer (TNBC) is an aggressive disease which currently has no effective therapeutic targets and prominent biomarkers. The Sperm Associated antigen 5 (SPAG5) is a mitotic spindle associated protein with oncogenic function in several human cancers. In TNBC, increased SPAG5 expression has been associated with tumor progression, chemoresistance, relapse, and poor clinical outcome. Here we show that high SPAG5 expression in TNBC is regulated by coordinated activity of YAP, mutant p53 and MYC. Depletion of YAP or mutant p53 proteins reduced SPAG5 expression and the recruitment of MYC onto SPAG5 promoter. Targeting of MYC also reduced SPAG5 expression and concomitantly tumorigenicity of TNBC cells. These effects of MYC targeting were synergized with cytotoxic chemotherapy and markedly reduced TNBC oncogenicity in SPAG5-expression dependent manner. These results suggest that mutant p53-MYC-SPAG5 expression can be considered as bona fide predictors of patient's outcome, and reliable biomarkers for effective anticancer therapies.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":null,"pages":null},"PeriodicalIF":8.1,"publicationDate":"2024-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11336084/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142008300","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-20DOI: 10.1038/s41419-024-06953-7
María A Rodríguez-Hernández, Raquel Chapresto-Garzón, Miryam Cadenas, Elena Navarro-Villarán, María Negrete, Miguel A Gómez-Bravo, Victor M Victor, Francisco J Padillo, Jordi Muntané
{"title":"Correction to: Differential effectiveness of tyrosine kinase inhibitors in 2D/3D culture according to cell differentiation, p53 status and mitochondrial respiration in liver cancer cells.","authors":"María A Rodríguez-Hernández, Raquel Chapresto-Garzón, Miryam Cadenas, Elena Navarro-Villarán, María Negrete, Miguel A Gómez-Bravo, Victor M Victor, Francisco J Padillo, Jordi Muntané","doi":"10.1038/s41419-024-06953-7","DOIUrl":"10.1038/s41419-024-06953-7","url":null,"abstract":"","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":null,"pages":null},"PeriodicalIF":8.1,"publicationDate":"2024-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11336236/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142008378","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-20DOI: 10.1038/s41419-024-06997-9
Yueqing Han, Qi Gao, Yating Xu, Ke Chen, Rongxin Li, Weiran Guo, Shuzhen Wang
Sulfenylation is a reversible oxidative posttranslational modification (PTM) of proteins on cysteine residues. Despite the dissection of various biological functions of cysteine sulfenylation, its roles in hepatic fibrosis remain elusive. Here, we report that EphB2, a receptor tyrosine kinase previously implicated in liver fibrosis, is regulated by cysteine sulfenylation during the fibrotic progression of liver. Specifically, EphB2 is sulfenylated at the residues of Cys636 and Cys862 in activated hepatic stellate cells (HSCs), leading to the elevation of tyrosine kinase activity and protein stability of EphB2 and stronger interactions with focal adhesion kinase for the activation of downstream mitogen-activated protein kinase signaling. The inhibitions of both EphB2 kinase activity and cysteine sulfenylation by idebenone (IDE), a marketed drug with potent antioxidant activity, can markedly suppress the activation of HSCs and ameliorate hepatic injury in two well-recognized mouse models of liver fibrosis. Collectively, this study reveals cysteine sulfenylation as a new type of PTM for EphB2 and sheds a light on the therapeutic potential of IDE for the treatment of liver fibrosis.
{"title":"Cysteine sulfenylation contributes to liver fibrosis via the regulation of EphB2-mediated signaling.","authors":"Yueqing Han, Qi Gao, Yating Xu, Ke Chen, Rongxin Li, Weiran Guo, Shuzhen Wang","doi":"10.1038/s41419-024-06997-9","DOIUrl":"10.1038/s41419-024-06997-9","url":null,"abstract":"<p><p>Sulfenylation is a reversible oxidative posttranslational modification (PTM) of proteins on cysteine residues. Despite the dissection of various biological functions of cysteine sulfenylation, its roles in hepatic fibrosis remain elusive. Here, we report that EphB2, a receptor tyrosine kinase previously implicated in liver fibrosis, is regulated by cysteine sulfenylation during the fibrotic progression of liver. Specifically, EphB2 is sulfenylated at the residues of Cys636 and Cys862 in activated hepatic stellate cells (HSCs), leading to the elevation of tyrosine kinase activity and protein stability of EphB2 and stronger interactions with focal adhesion kinase for the activation of downstream mitogen-activated protein kinase signaling. The inhibitions of both EphB2 kinase activity and cysteine sulfenylation by idebenone (IDE), a marketed drug with potent antioxidant activity, can markedly suppress the activation of HSCs and ameliorate hepatic injury in two well-recognized mouse models of liver fibrosis. Collectively, this study reveals cysteine sulfenylation as a new type of PTM for EphB2 and sheds a light on the therapeutic potential of IDE for the treatment of liver fibrosis.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":null,"pages":null},"PeriodicalIF":8.1,"publicationDate":"2024-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11335765/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142008298","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}