Pub Date : 2025-01-04DOI: 10.1016/j.cellsig.2024.111586
Yue Zhou , Maoye Wang , Yu Qian , Dan Yu , Jiahui Zhang , Min Fu , Xiaoxin Zhang , Rong Qin , Runbi Ji , Xu Zhang , Jianmei Gu
Peroxiredoxin 2 (PRDX2) is an antioxidant enzyme that has been reported to be overexpressed in various cancers. However, the role of PRDX2 in gastric cancer progression and its underlying mechanism remains unclear. Herein, we revealed the function of PRDX2 in gastric cancer progression and explored its molecule mechanism. We identified that PRDX2 was upregulated and associated with poor prognosis in gastric cancer. The knockdown of PRDX2 inhibited the proliferation, migration and invasion of gastric cancer cells in vitro and suppressed tumor growth in vivo. Mechanistically, PRDX2 interacted with PKM2 (pyruvate kinase isozyme type M2) and protected PKM2 from ubiquitination and degradation, which enhanced glycolysis in gastric cancer cells. The interaction between PRDX2 and PKM2 also enhanced the binding affinity between PKM2 and importin α5, which induced PKM2 nuclear translocation and activated STAT3 signaling pathway. In addition, STAT3 (signal transducer and activator of transcription 3) was identified to bind to PRDX2 gene promoter and upregulate PRDX2 expression, which forms a positive regulatory feedback loop in gastric cancer cells. The present study unravels the biological role of PRDX2 in cancer progression and illustrates the underlying molecular mechanism, which may provide a potential therapeutic target for gastric cancer.
过氧化氧还蛋白2 （PRDX2）是一种抗氧化酶，据报道在多种癌症中过度表达。然而，PRDX2在胃癌进展中的作用及其潜在机制尚不清楚。本文揭示了PRDX2在胃癌进展中的作用，并探讨了其分子机制。我们发现PRDX2在胃癌中表达上调并与不良预后相关。PRDX2基因在体外抑制胃癌细胞的增殖、迁移和侵袭，在体内抑制肿瘤生长。机制上，PRDX2与PKM2（丙酮酸激酶同工酶型M2）相互作用，保护PKM2免于泛素化和降解，从而促进胃癌细胞的糖酵解。PRDX2与PKM2的相互作用也增强了PKM2与输入蛋白α5的结合亲和力，诱导PKM2核易位，激活STAT3信号通路。此外，还发现STAT3 （signal transducer and activator of transcription 3）与PRDX2基因启动子结合，上调PRDX2的表达，在胃癌细胞中形成正调节反馈回路。本研究揭示了PRDX2在肿瘤进展中的生物学作用，并阐明了其潜在的分子机制，可能为胃癌的治疗提供潜在的靶点。
{"title":"PRDX2 promotes gastric cancer progression by forming a feedback loop with PKM2/STAT3 axis","authors":"Yue Zhou , Maoye Wang , Yu Qian , Dan Yu , Jiahui Zhang , Min Fu , Xiaoxin Zhang , Rong Qin , Runbi Ji , Xu Zhang , Jianmei Gu","doi":"10.1016/j.cellsig.2024.111586","DOIUrl":"10.1016/j.cellsig.2024.111586","url":null,"abstract":"<div><div>Peroxiredoxin 2 (PRDX2) is an antioxidant enzyme that has been reported to be overexpressed in various cancers. However, the role of PRDX2 in gastric cancer progression and its underlying mechanism remains unclear. Herein, we revealed the function of PRDX2 in gastric cancer progression and explored its molecule mechanism. We identified that PRDX2 was upregulated and associated with poor prognosis in gastric cancer. The knockdown of PRDX2 inhibited the proliferation, migration and invasion of gastric cancer cells <em>in vitro</em> and suppressed tumor growth <em>in vivo</em>. Mechanistically, PRDX2 interacted with PKM2 (pyruvate kinase isozyme type M2) and protected PKM2 from ubiquitination and degradation, which enhanced glycolysis in gastric cancer cells. The interaction between PRDX2 and PKM2 also enhanced the binding affinity between PKM2 and importin α5, which induced PKM2 nuclear translocation and activated STAT3 signaling pathway. In addition, STAT3 (signal transducer and activator of transcription 3) was identified to bind to PRDX2 gene promoter and upregulate PRDX2 expression, which forms a positive regulatory feedback loop in gastric cancer cells. The present study unravels the biological role of PRDX2 in cancer progression and illustrates the underlying molecular mechanism, which may provide a potential therapeutic target for gastric cancer.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"127 ","pages":"Article 111586"},"PeriodicalIF":4.4,"publicationDate":"2025-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142961992","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}
Pub Date : 2025-01-03DOI: 10.1016/j.cellsig.2024.111584
John Y. Kwon, Renzo E. Vera, Martin E. Fernandez-Zapico
The tumor microenvironment (TME) has been linked with the pathogenesis of pancreatic ductal adenocarcinoma (PDAC), the most common histological subtype of pancreatic cancer. A central component of the TME are cancer-associated fibroblasts (CAFs), which can either suppress or promote tumor growth in a context-dependent manner. In this review, we will discuss the multi-faceted roles of CAFs in tumor-stroma interactions influencing cancer initiation, progression and therapeutic response.
{"title":"The multi-faceted roles of cancer-associated fibroblasts in pancreatic cancer","authors":"John Y. Kwon, Renzo E. Vera, Martin E. Fernandez-Zapico","doi":"10.1016/j.cellsig.2024.111584","DOIUrl":"10.1016/j.cellsig.2024.111584","url":null,"abstract":"<div><div>The tumor microenvironment (TME) has been linked with the pathogenesis of pancreatic ductal adenocarcinoma (PDAC), the most common histological subtype of pancreatic cancer. A central component of the TME are cancer-associated fibroblasts (CAFs), which can either suppress or promote tumor growth in a context-dependent manner. In this review, we will discuss the multi-faceted roles of CAFs in tumor-stroma interactions influencing cancer initiation, progression and therapeutic response.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"127 ","pages":"Article 111584"},"PeriodicalIF":4.4,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142930459","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}
Pub Date : 2025-01-03DOI: 10.1016/j.cellsig.2024.111583
Ruipeng Bian , Yingying Shang , Nahua Xu , Baiping Liu , Yanni Ma , Hui Li , Jieping Chen , Qi Yao
Acute Myeloid Leukemia (AML) are challenging blood cancers with limited long-term survival rates, necessitating novel therapeutic strategies. This study explored the role of Histone deacetylase (HDAC) inhibitors in enhancing ferroptosis in AML cells by modulating iron metabolism. We demonstrated that HDAC inhibitors (Entinostat and Vorinostat) sensitize AML cells to ferroptosis both in vitro and in vivo. Mechanistically, we show that HDAC inhibitor treatment upregulated the expression of iron metabolism genes that lead to increased labile iron pool. Notably, NCOA4, a ferritin degradation mediator, and HMOX1/2 proteins, involved in heme breakdown, were identified as critical contributors to this process. The functional role of these genes was confirmed through CRISPR-Cas9 mediated knockouts, which significantly rescued cells from HDAC-induced ferroptosis sensitivity. Our results suggest a novel therapeutic approach for AML, where combining HDAC inhibitors with ferroptosis inducers could exploit the disrupted iron metabolism in AML cells. This study highlights the potential of HDAC inhibitors to modulate iron metabolism pathways, offering new insights into the treatment of these malignancies.
{"title":"HDAC inhibitor enhances ferroptosis susceptibility of AML cells by stimulating iron metabolism","authors":"Ruipeng Bian , Yingying Shang , Nahua Xu , Baiping Liu , Yanni Ma , Hui Li , Jieping Chen , Qi Yao","doi":"10.1016/j.cellsig.2024.111583","DOIUrl":"10.1016/j.cellsig.2024.111583","url":null,"abstract":"<div><div>Acute Myeloid Leukemia (AML) are challenging blood cancers with limited long-term survival rates, necessitating novel therapeutic strategies. This study explored the role of Histone deacetylase (HDAC) inhibitors in enhancing ferroptosis in AML cells by modulating iron metabolism. We demonstrated that HDAC inhibitors (Entinostat and Vorinostat) sensitize AML cells to ferroptosis both in vitro and in vivo. Mechanistically, we show that HDAC inhibitor treatment upregulated the expression of iron metabolism genes that lead to increased labile iron pool. Notably, NCOA4, a ferritin degradation mediator, and HMOX1/2 proteins, involved in heme breakdown, were identified as critical contributors to this process. The functional role of these genes was confirmed through CRISPR-Cas9 mediated knockouts, which significantly rescued cells from HDAC-induced ferroptosis sensitivity. Our results suggest a novel therapeutic approach for AML, where combining HDAC inhibitors with ferroptosis inducers could exploit the disrupted iron metabolism in AML cells. This study highlights the potential of HDAC inhibitors to modulate iron metabolism pathways, offering new insights into the treatment of these malignancies.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"127 ","pages":"Article 111583"},"PeriodicalIF":4.4,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142930530","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}
Pub Date : 2025-01-02DOI: 10.1016/j.cellsig.2024.111587
Rukhsana Kausar , Nga Thi Thanh Nguyen , Truc Phan Hoang Le , Jae Hyung Kim , Sang Yoon Lee
Oxidative stress caused by reactive oxygen species (ROS) and superoxides is linked to various cancer-related biological events. Extracellular superoxide dismutase (SOD3), an antioxidant enzyme that removes superoxides, contributes to redox homeostasis and has the potential to regulate tumorigenesis. Histone deacetylase 6 (HDAC6), a major HDAC isoform responsible for mediating the deacetylation of non-histone protein substrates, also plays a role in cancer progression. In this study, we examined the potential effects of HDAC6 inhibition on SOD3 expression in head and neck cancer (HNC) cells and its impact on cell proliferation, which remains unaddressed. We found that functional inactivation of HDAC6, through the use of chemical inhibitors such as tubastatin A (TubA), gene knockdown, or overexpression of an inactive mutant, strongly upregulated protein and mRNA levels of SOD3 in HNC cell lines FaDu and Detroit562. Mechanistically, TubA induced acetylation of the transcription factor Sp1 at Lys703, which consequently enhanced its binding to the SOD3 proximal promoter region and increased SOD3 expression. An acetylation-defective Sp1 mutant (K703R) was much less effective in inducing SOD3 expression compared to wild-type Sp1. TubA reduced intracellular ROS and superoxide levels, and this antioxidative effect was attenuated in SOD3 knockdown cells. Similar to the changes in ROS levels, HDAC6 inhibition as well as SOD3 overexpression suppressed cell proliferation and the stimulatory phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2), whereas SOD3 knockdown produced opposite effects in both resting and TubA-treated conditions. In addition, SOD3 overexpression prevented ROS-induced ERK1/2 phosphorylation and enhanced the protein stability of mitogen-activated protein kinase phosphatase 1 (MKP1), thereby counteracting ERK1/2 phosphorylation. We further showed that SOD3-mediated ERK1/2 dephosphorylation was moderated in MKP1 knockdown cells. Collectively, these results suggest that HDAC6 inhibition elicits anticancer effects on HNC cells by promoting Sp1 acetylation-dependent SOD3 upregulation, leading to MKP1 stabilization and subsequent ERK1/2 inactivation.
活性氧（ROS）和超氧化物引起的氧化应激与多种癌症相关的生物事件有关。细胞外超氧化物歧化酶（SOD3）是一种去除超氧化物的抗氧化酶，有助于氧化还原稳态，并具有调节肿瘤发生的潜力。组蛋白去乙酰化酶6 （HDAC6）是一种主要的HDAC异构体，负责介导非组蛋白底物的去乙酰化，也在癌症进展中发挥作用。在这项研究中，我们研究了HDAC6抑制头颈癌（HNC）细胞中SOD3表达的潜在影响及其对细胞增殖的影响，这一问题尚未得到解决。我们发现，通过使用化学抑制剂，如tubastatin A (TubA)，基因敲低或过表达失活突变体，HDAC6的功能失活，在HNC细胞系FaDu和Detroit562中，SOD3蛋白和mRNA水平强烈上调。在机制上，TubA诱导转录因子Sp1在Lys703位点乙酰化，从而增强其与SOD3近端启动子区域的结合，增加SOD3的表达。与野生型Sp1相比，乙酰化缺陷Sp1突变体（K703R）诱导SOD3表达的效果要差得多。TubA降低了细胞内ROS和超氧化物水平，而这种抗氧化作用在SOD3敲除的细胞中减弱。与ROS水平的变化类似，HDAC6抑制和SOD3过表达抑制细胞增殖和刺激细胞外信号调节激酶1/2 （ERK1/2）的磷酸化，而SOD3敲低在静息和tuba处理条件下均产生相反的作用。此外，SOD3过表达可阻止ros诱导的ERK1/2磷酸化，增强丝裂原活化的蛋白激酶磷酸酶1 （MKP1）的蛋白稳定性，从而抵消ERK1/2磷酸化。我们进一步发现sod3介导的ERK1/2去磷酸化在MKP1敲低的细胞中得到了减缓。总之，这些结果表明，HDAC6抑制通过促进Sp1乙酰化依赖性SOD3上调，导致MKP1稳定和随后的ERK1/2失活，从而引发对HNC细胞的抗癌作用。
{"title":"Inhibition of HDAC6 elicits anticancer effects on head and neck cancer cells through Sp1/SOD3/MKP1 signaling axis to downregulate ERK phosphorylation","authors":"Rukhsana Kausar , Nga Thi Thanh Nguyen , Truc Phan Hoang Le , Jae Hyung Kim , Sang Yoon Lee","doi":"10.1016/j.cellsig.2024.111587","DOIUrl":"10.1016/j.cellsig.2024.111587","url":null,"abstract":"<div><div>Oxidative stress caused by reactive oxygen species (ROS) and superoxides is linked to various cancer-related biological events. Extracellular superoxide dismutase (SOD3), an antioxidant enzyme that removes superoxides, contributes to redox homeostasis and has the potential to regulate tumorigenesis. Histone deacetylase 6 (HDAC6), a major HDAC isoform responsible for mediating the deacetylation of non-histone protein substrates, also plays a role in cancer progression. In this study, we examined the potential effects of HDAC6 inhibition on SOD3 expression in head and neck cancer (HNC) cells and its impact on cell proliferation, which remains unaddressed. We found that functional inactivation of HDAC6, through the use of chemical inhibitors such as tubastatin A (TubA), gene knockdown, or overexpression of an inactive mutant, strongly upregulated protein and mRNA levels of SOD3 in HNC cell lines FaDu and Detroit562. Mechanistically, TubA induced acetylation of the transcription factor Sp1 at Lys703, which consequently enhanced its binding to the SOD3 proximal promoter region and increased SOD3 expression. An acetylation-defective Sp1 mutant (K703R) was much less effective in inducing SOD3 expression compared to wild-type Sp1. TubA reduced intracellular ROS and superoxide levels, and this antioxidative effect was attenuated in SOD3 knockdown cells. Similar to the changes in ROS levels, HDAC6 inhibition as well as SOD3 overexpression suppressed cell proliferation and the stimulatory phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2), whereas SOD3 knockdown produced opposite effects in both resting and TubA-treated conditions. In addition, SOD3 overexpression prevented ROS-induced ERK1/2 phosphorylation and enhanced the protein stability of mitogen-activated protein kinase phosphatase 1 (MKP1), thereby counteracting ERK1/2 phosphorylation. We further showed that SOD3-mediated ERK1/2 dephosphorylation was moderated in MKP1 knockdown cells. Collectively, these results suggest that HDAC6 inhibition elicits anticancer effects on HNC cells by promoting Sp1 acetylation-dependent SOD3 upregulation, leading to MKP1 stabilization and subsequent ERK1/2 inactivation.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"127 ","pages":"Article 111587"},"PeriodicalIF":4.4,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142926547","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}
Pub Date : 2024-12-31DOI: 10.1016/j.cellsig.2024.111585
Longhui Xie , Dekun Song , Zhengsheng Ouyang , Yinkuan Ning , Xintao Liu , Lai Li , Wangning Xia , Yang Yang
Hepatocellular carcinoma (HCC) is associated with a dismal prognosis, primarily due to its high rates of metastasis and recurrence. Metabolic reprogramming, specifically enhanced glycolysis, is a prominent feature of cancer progression. This study identifies ubiquitin-specific peptidase 27 X-linked (USP27) as a significant regulator of glycolysis in HCC. We demonstrate that USP27 stabilizes PFKFB3, a key glycolytic enzyme, through deubiquitination, thereby increasing glycolytic activity and facilitating tumor progression. Furthermore, we reveal that CTCF, a well-known transcription factor, directly binds to the USP27 promoter and upregulates its expression, thereby establishing a connection between transcriptional regulation and metabolic reprogramming in HCC. Knockdown of USP27 or CTCF in HCC cells considerably decreased glycolysis and proliferation, while overexpression had the opposite effect. In vivo studies confirmed that USP27 knockdown suppresses HCC growth and metastasis. Our findings establish the CTCF/USP27/PFKFB3 axis as a novel mechanism driving HCC progression through glycolysis, indicating that targeting this pathway could offer new therapeutic opportunities. These results provide valuable insights into the molecular mechanisms underlying HCC and emphasize the potential of targeting USP27-mediated metabolic pathways as a strategy for cancer treatment.
{"title":"USP27 promotes glycolysis and hepatocellular carcinoma progression by stabilizing PFKFB3 through deubiquitination","authors":"Longhui Xie , Dekun Song , Zhengsheng Ouyang , Yinkuan Ning , Xintao Liu , Lai Li , Wangning Xia , Yang Yang","doi":"10.1016/j.cellsig.2024.111585","DOIUrl":"10.1016/j.cellsig.2024.111585","url":null,"abstract":"<div><div>Hepatocellular carcinoma (HCC) is associated with a dismal prognosis, primarily due to its high rates of metastasis and recurrence. Metabolic reprogramming, specifically enhanced glycolysis, is a prominent feature of cancer progression. This study identifies ubiquitin-specific peptidase 27 X-linked (USP27) as a significant regulator of glycolysis in HCC. We demonstrate that USP27 stabilizes PFKFB3, a key glycolytic enzyme, through deubiquitination, thereby increasing glycolytic activity and facilitating tumor progression. Furthermore, we reveal that CTCF, a well-known transcription factor, directly binds to the USP27 promoter and upregulates its expression, thereby establishing a connection between transcriptional regulation and metabolic reprogramming in HCC. Knockdown of USP27 or CTCF in HCC cells considerably decreased glycolysis and proliferation, while overexpression had the opposite effect. In vivo studies confirmed that USP27 knockdown suppresses HCC growth and metastasis. Our findings establish the CTCF/USP27/PFKFB3 axis as a novel mechanism driving HCC progression through glycolysis, indicating that targeting this pathway could offer new therapeutic opportunities. These results provide valuable insights into the molecular mechanisms underlying HCC and emphasize the potential of targeting USP27-mediated metabolic pathways as a strategy for cancer treatment.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"127 ","pages":"Article 111585"},"PeriodicalIF":4.4,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142920911","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}
Pub Date : 2024-12-27DOI: 10.1016/j.cellsig.2024.111582
Gaomeng Luo , Wenxuan Hu , Jian Yang , Hao Ding , Chun Xu , Xin Tong , Cheng Ding , Jun Zhao
Exploring new oncotargets essential for lung adenocarcinoma (LUAD) cell growth is important. Here the bioinformatical studies revealed that Gαi3 expression is elevated in LUAD tissues and its overexpression correlates with poor survival of the patients. Moreover, overexpression of Gαi3 mRNA and protein was detected in LUAD tissues of patients as well as in primary/immortalized LUAD cells. In both primary and immortalized LUAD cells, genetic silencing (by viral shRNA) or knockout (“KO”, through CRISPR/Cas9 method) of Gαi3 potently inhibited LUAD cell proliferation and mobility. The results of caspase-3 activity assay, caspase-9 activity assay, histone DNA ELISA, TUNEL nuclear staining and Annexin V staining showed that inhibition of Gαi3 expression promoted apoptosis. In addition, a significant decrease in mitochondrial membrane potential was found in Gαi3-deficient LUAD cells by JC-1 staining. Overexpression of Gαi3 strengthened the proliferation and migration of LUAD cell. Gene set enrichment analysis revealed that Gαi3 was closely related to PI3k/Akt/mTOR, which we validated experimentally. Akt-S6K phosphorylation was downregulated following Gαi3 silencing or KO, but augmented after Gαi3 overexpression in primary LUAD cells. Restoring Akt-S6K phosphorylation by a S473D constitutively-active mutant Akt1 ameliorated Gαi3 KO-induced LUAD cell proliferation inhibition, migration suppression and apoptosis. In vivo, the growth of subcutaneous LUAD xenografts was largely inhibited after intratumoral injection of Gαi3 shRNA-expressing adeno-associated virus (AAV). Gαi3 downregulation, Akt-mTOR inhibition, proliferation inactivation and apoptosis were detected in the Gαi3 shRNA-treated LUAD xenografts. Together, targeting Gαi3 potently inhibited LUAD cell growth in vitro and in vivo.
{"title":"Identification of G protein subunit alpha i3 as a promising oncotarget of LUAD","authors":"Gaomeng Luo , Wenxuan Hu , Jian Yang , Hao Ding , Chun Xu , Xin Tong , Cheng Ding , Jun Zhao","doi":"10.1016/j.cellsig.2024.111582","DOIUrl":"10.1016/j.cellsig.2024.111582","url":null,"abstract":"<div><div>Exploring new oncotargets essential for lung adenocarcinoma (LUAD) cell growth is important. Here the bioinformatical studies revealed that <em>Gαi3</em> expression is elevated in LUAD tissues and its overexpression correlates with poor survival of the patients. Moreover, overexpression of <em>Gαi3</em> mRNA and protein was detected in LUAD tissues of patients as well as in primary/immortalized LUAD cells. In both primary and immortalized LUAD cells, genetic silencing (by viral shRNA) or knockout (“KO”, through CRISPR/Cas9 method) of Gαi3 potently inhibited LUAD cell proliferation and mobility. The results of caspase-3 activity assay, caspase-9 activity assay, histone DNA ELISA, TUNEL nuclear staining and Annexin V staining showed that inhibition of Gαi3 expression promoted apoptosis. In addition, a significant decrease in mitochondrial membrane potential was found in Gαi3-deficient LUAD cells by JC-1 staining. Overexpression of Gαi3 strengthened the proliferation and migration of LUAD cell. Gene set enrichment analysis revealed that <em>Gαi3</em> was closely related to PI3k/Akt/mTOR, which we validated experimentally. Akt-S6K phosphorylation was downregulated following Gαi3 silencing or KO, but augmented after Gαi3 overexpression in primary LUAD cells. Restoring Akt-S6K phosphorylation by a S473D constitutively-active mutant Akt1 ameliorated Gαi3 KO-induced LUAD cell proliferation inhibition, migration suppression and apoptosis. <em>In vivo</em>, the growth of subcutaneous LUAD xenografts was largely inhibited after intratumoral injection of Gαi3 shRNA-expressing adeno-associated virus (AAV). Gαi3 downregulation, Akt-mTOR inhibition, proliferation inactivation and apoptosis were detected in the Gαi3 shRNA-treated LUAD xenografts. Together, targeting Gαi3 potently inhibited LUAD cell growth <em>in vitro</em> and <em>in vivo</em>.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"127 ","pages":"Article 111582"},"PeriodicalIF":4.4,"publicationDate":"2024-12-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142902623","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}
Pub Date : 2024-12-27DOI: 10.1016/j.cellsig.2024.111579
Yuanyuan Li , Yuxiu Lin , Zhi Chen , Wei Ji , Huan Liu
The aging process is associated with a loss of bone mass and an accumulation of senescent cells, which is under epigenetic control. Morphological and molecular analysis revealed a notable reduction in bone mass and alveolar crest height in aged mice, accompanied by increased levels of senescent mouse jaw bone marrow stem cells (mJBMSCs). To investigate whether specific transcription factors are involved, assay for transposase-accessible chromatin with sequencing (ATAC-seq) was performed on mJBMSCs isolated from 2-, 4-, 8-, and 20-month-old mice. In 20-month-old mJBMSCs, increased chromatin accessibility was observed alongside elevated expression of activating transcription factor 2 (ATF2) in both cells and alveolar bone. Silencing Atf2 in mJBMSCs failed to reverse physiological aging, but delayed replication stress and pamidronate (PAM) induced senescence. The analysis of ATAC-seq and RNA sequencing indicated that the differentially expressed genes upregulated by PAM but downregulated by ATF2 deficiency were related to some key biological processes, including negative regulation of cell proliferation, inflammatory response, adipogenesis, and cellular senescence. The dual-luciferase assay was conducted to demonstrate that ATF2 enhances Cdkn2a transcription by binding to its promoter region. Our findings suggest significant chromatin alterations in aged mJBMSCs, positioning ATF2 as a potential target for combating externally induced senescence.
{"title":"Deficiency of ATF2 retards senescence induced by replication stress and pamidronate in mouse jaw bone marrow stem cells","authors":"Yuanyuan Li , Yuxiu Lin , Zhi Chen , Wei Ji , Huan Liu","doi":"10.1016/j.cellsig.2024.111579","DOIUrl":"10.1016/j.cellsig.2024.111579","url":null,"abstract":"<div><div>The aging process is associated with a loss of bone mass and an accumulation of senescent cells, which is under epigenetic control. Morphological and molecular analysis revealed a notable reduction in bone mass and alveolar crest height in aged mice, accompanied by increased levels of senescent mouse jaw bone marrow stem cells (mJBMSCs). To investigate whether specific transcription factors are involved, assay for transposase-accessible chromatin with sequencing (ATAC-seq) was performed on mJBMSCs isolated from 2-, 4-, 8-, and 20-month-old mice. In 20-month-old mJBMSCs, increased chromatin accessibility was observed alongside elevated expression of activating transcription factor 2 (ATF2) in both cells and alveolar bone. Silencing <em>Atf2</em> in mJBMSCs failed to reverse physiological aging, but delayed replication stress and pamidronate (PAM) induced senescence. The analysis of ATAC-seq and RNA sequencing indicated that the differentially expressed genes upregulated by PAM but downregulated by ATF2 deficiency were related to some key biological processes, including negative regulation of cell proliferation, inflammatory response, adipogenesis, and cellular senescence. The dual-luciferase assay was conducted to demonstrate that ATF2 enhances <em>Cdkn2a</em> transcription by binding to its promoter region. Our findings suggest significant chromatin alterations in aged mJBMSCs, positioning ATF2 as a potential target for combating externally induced senescence.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"127 ","pages":"Article 111579"},"PeriodicalIF":4.4,"publicationDate":"2024-12-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142902445","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}
Pub Date : 2024-12-26DOI: 10.1016/j.cellsig.2024.111581
Dehuan Liang , Danni Wang , Xinyue Zheng , Heng Xiang , Sujuan Liu , Chunxia Yu , Jiatong Tian , Jianxiong Ma , Yanmei Niu
This study aimed to investigate the underlying mechanisms by which physical exercise mitigates muscle atrophy induced by Dexamethasone (Dex). A muscle atrophy model was established in the mouse C2C12 cell line and 8-week-old mice treated with Dex, with subsequent verification of phenotype and atrogene expression. The potential benefits of combined aerobic and resistance exercise in mitigating muscle atrophy were then examined. To elucidate the involvement of Histone deacetylase 4 (HDAC4) in the protective effects of exercise against muscle loss, a combination of RT-PCR, Western blotting, immunoprecipitation, and immunofluorescence staining techniques were employed. The upregulation of HDAC4 was observed following Dex-induced muscle atrophy in vitro and in vivo. Inhibition of HDAC4 in C2C12 cells resulted in an increase in myotube diameter and fusion index, along with a decrease in the expression of Atrogin-1 and MuRF1. Treatment with Tasquinimod, an HDAC4 inhibitor, effectively prevented muscle wasting and dysfunction in mice induced by Dex. After a 6-week exercise intervention, the Dex-Exercise group exhibited significant improvements in body fat level, hyperinsulinemia, muscle mass and function in comparison to the Dex-Sedentary group. Mechanistically, we discovered that HDAC4 bound to and deacetylated Forkhead box protein O 3a (FoxO3a) within the nucleus, leading to decreased phosphorylation of FoxO3a at Ser 253. This interaction subsequently facilitated the expression of downstream atrogene Atrogin-1 and MuRF1, resulting in muscle atrophy. Conversely, exercise was found to potentially mitigate muscle atrophy by inhibiting the HDAC4/FoxO3a pathway. These findings suggest that HDAC4 may be a potential therapeutic target for exercise to combat Dex-induced muscle atrophy.
本研究旨在探讨体育锻炼减轻地塞米松（Dex）所致肌肉萎缩的潜在机制。在小鼠C2C12细胞系和8周龄小鼠中建立肌萎缩模型，随后验证表型和atrogene表达。然后研究了有氧和阻力联合运动在减轻肌肉萎缩方面的潜在益处。为了阐明组蛋白去乙酰化酶4 （HDAC4）在运动对肌肉损失的保护作用中的作用，我们采用了RT-PCR、Western blotting、免疫沉淀和免疫荧光染色技术相结合的方法。在体外和体内观察dex诱导的肌肉萎缩后HDAC4表达上调。抑制HDAC4在C2C12细胞中导致肌管直径和融合指数增加，Atrogin-1和MuRF1的表达降低。用HDAC4抑制剂Tasquinimod治疗可有效预防右美托咪定引起的小鼠肌肉萎缩和功能障碍。经过6周的运动干预，与dex -久坐组相比，Dex-Exercise组在体脂水平、高胰岛素血症、肌肉质量和功能方面表现出显著改善。在机制上，我们发现HDAC4与细胞核内叉头盒蛋白O3a （FoxO3a）结合并去乙酰化，导致FoxO3a Ser 253磷酸化降低。这种相互作用随后促进了下游atrogene -1和MuRF1的表达，导致肌肉萎缩。相反，研究发现运动可能通过抑制HDAC4/FoxO3a通路来缓解肌肉萎缩。这些发现表明，HDAC4可能是运动对抗dex诱导的肌肉萎缩的潜在治疗靶点。
{"title":"Aerobic plus resistance exercise attenuates skeletal muscle atrophy induced by dexamethasone through the HDAC4/FoxO3a pathway","authors":"Dehuan Liang , Danni Wang , Xinyue Zheng , Heng Xiang , Sujuan Liu , Chunxia Yu , Jiatong Tian , Jianxiong Ma , Yanmei Niu","doi":"10.1016/j.cellsig.2024.111581","DOIUrl":"10.1016/j.cellsig.2024.111581","url":null,"abstract":"<div><div>This study aimed to investigate the underlying mechanisms by which physical exercise mitigates muscle atrophy induced by Dexamethasone (Dex). A muscle atrophy model was established in the mouse C2C12 cell line and 8-week-old mice treated with Dex, with subsequent verification of phenotype and atrogene expression. The potential benefits of combined aerobic and resistance exercise in mitigating muscle atrophy were then examined. To elucidate the involvement of Histone deacetylase 4 (HDAC4) in the protective effects of exercise against muscle loss, a combination of RT-PCR, Western blotting, immunoprecipitation, and immunofluorescence staining techniques were employed. The upregulation of HDAC4 was observed following Dex-induced muscle atrophy in vitro and in vivo. Inhibition of HDAC4 in C2C12 cells resulted in an increase in myotube diameter and fusion index, along with a decrease in the expression of Atrogin-1 and MuRF1. Treatment with Tasquinimod, an HDAC4 inhibitor, effectively prevented muscle wasting and dysfunction in mice induced by Dex. After a 6-week exercise intervention, the Dex-Exercise group exhibited significant improvements in body fat level, hyperinsulinemia, muscle mass and function in comparison to the Dex-Sedentary group. Mechanistically, we discovered that HDAC4 bound to and deacetylated Forkhead box protein O 3a (FoxO3a) within the nucleus, leading to decreased phosphorylation of FoxO3a at Ser 253. This interaction subsequently facilitated the expression of downstream atrogene Atrogin-1 and MuRF1, resulting in muscle atrophy. Conversely, exercise was found to potentially mitigate muscle atrophy by inhibiting the HDAC4/FoxO3a pathway. These findings suggest that HDAC4 may be a potential therapeutic target for exercise to combat Dex-induced muscle atrophy.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"127 ","pages":"Article 111581"},"PeriodicalIF":4.4,"publicationDate":"2024-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142892533","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}
Pub Date : 2024-12-26DOI: 10.1016/j.cellsig.2024.111580
Zexun Wang , Wangqing Sun , Kai Zhang , Xianjin Ke , Zhongqun Wang
Atherosclerotic cardiovascular and cerebrovascular diseases are the number one killer of human health. In view of the important role of mitochondria in the formation and evolution of atherosclerosis, our manuscript aims to comprehensively elaborate the relationship between mitochondria and the formation and evolution of atherosclerosis from the aspects of mitochondrial dynamics, mitochondria-organelle interaction (communication), mitochondria and cell death, mitochondria and vascular smooth muscle cell phenotypic switch, etc., which is combined with genome, transcriptome and proteome, in order to provide new ideas for the pathogenesis of atherosclerosis and the diagnosis and treatment of related diseases.
{"title":"New insights into the relationship of mitochondrial metabolism and atherosclerosis","authors":"Zexun Wang , Wangqing Sun , Kai Zhang , Xianjin Ke , Zhongqun Wang","doi":"10.1016/j.cellsig.2024.111580","DOIUrl":"10.1016/j.cellsig.2024.111580","url":null,"abstract":"<div><div>Atherosclerotic cardiovascular and cerebrovascular diseases are the number one killer of human health. In view of the important role of mitochondria in the formation and evolution of atherosclerosis, our manuscript aims to comprehensively elaborate the relationship between mitochondria and the formation and evolution of atherosclerosis from the aspects of mitochondrial dynamics, mitochondria-organelle interaction (communication), mitochondria and cell death, mitochondria and vascular smooth muscle cell phenotypic switch, etc., which is combined with genome, transcriptome and proteome, in order to provide new ideas for the pathogenesis of atherosclerosis and the diagnosis and treatment of related diseases.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"127 ","pages":"Article 111580"},"PeriodicalIF":4.4,"publicationDate":"2024-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142892483","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}
Pub Date : 2024-12-24DOI: 10.1016/j.cellsig.2024.111578
Xiaorui Geng , Yongjin Wu , Zhiqiang Liu , Jiangqi Liu , Bailing Xie , Le Liu , Hanqing Zhang , Lihua Mo , Yu Liu , Xianhai Zeng , Pingchang Yang
•
Probiotic Clostridium butyricum DNA (CbDNA)-containing nasal instillations can attenuate experimental airway allergy
•
CbDNA has better effects on attenuating airway allergy than oral ingestion of live C. butyricum
•
CbDNA increases the expression of SARM1 and induces activated Th2 cell apoptosis
{"title":"Probiotic DNA alleviates experimental airway allergy","authors":"Xiaorui Geng , Yongjin Wu , Zhiqiang Liu , Jiangqi Liu , Bailing Xie , Le Liu , Hanqing Zhang , Lihua Mo , Yu Liu , Xianhai Zeng , Pingchang Yang","doi":"10.1016/j.cellsig.2024.111578","DOIUrl":"10.1016/j.cellsig.2024.111578","url":null,"abstract":"<div><div><ul><li><span>•</span><span><div>Probiotic <em>Clostridium butyricum</em> DNA (CbDNA)-containing nasal instillations can attenuate experimental airway allergy</div></span></li><li><span>•</span><span><div>CbDNA has better effects on attenuating airway allergy than oral ingestion of live <em>C. butyricum</em></div></span></li><li><span>•</span><span><div>CbDNA increases the expression of SARM1 and induces activated Th2 cell apoptosis</div></span></li></ul></div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"127 ","pages":"Article 111578"},"PeriodicalIF":4.4,"publicationDate":"2024-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142892543","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}
扫码关注我们
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号