Cellular signalling最新文献

{"title":"Mycobacterium manipulate glutaminase 1 mediated glutaminolysis to regulate macrophage autophagy for bacteria intracellular survival","authors":"Jialin Yu ,&nbsp;Na Yan ,&nbsp;Zhaoqian Gong ,&nbsp;Qinmei Ma ,&nbsp;Jing Liu ,&nbsp;Xiaoling Wu ,&nbsp;Guangcun Deng","doi":"10.1016/j.cellsig.2024.111422","DOIUrl":"10.1016/j.cellsig.2024.111422","url":null,"abstract":"<div><div>Autophagy plays a vital role in eliminating intracellular <em>mycobacterium</em>. It is regulated by multiple metabolic processes including glutaminolysis. Glutaminase 1 (GLS1) is the rate-limiting enzyme of glutaminolysis and has been reported to control intracellular Gln content. However, its function on regulating autophagy in <em>mycobacterium</em> infected macrophage is still obscure. Hence, the current study hired <em>mycobacterium</em> virulent strain <em>H37Rv</em> or attenuated strain BCG to infect macrophage and detected the changes in cell glutaminolysis. The function of GLS1 on regulating autophagy in <em>mycobacterium</em> infected macrophages was further investigated. The results showed that BCG infection promoted macrophage autophagy, enhanced glutaminolysis, reduced intracellular Gln content, accompanied with the up-regulation of GLS1. Conversely, <em>H37Rv</em> infection resulted in completely opposite effects. Meanwhile, knockdown of GLS1 increased Gln content and attenuated autophagy in BCG infected macrophages. In addition, the deprivation of Gln not only promoted the autophagy of <em>H37Rv</em> infected macrophages, but also abolished the effect of knockdown GLS1 on regulating BCG infection-induced mTOR activation or autophagy. To sum up, our study suggested that different virulent strains of mycobacterium infection have totally opposite effects on glutaminolysis and the expression of GLS1. Specifically, <em>mycobacterium</em> virulent strain reduced GLS1 expression and decreased Gln content but <em>mycobacterium</em> attenuated strain promoted GLS1 expression and enhanced Gln content. Furthermore, GLS1 inhibits the activation of the mTOR signaling pathway and promotes autophagy by decreasing Gln content.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"124 ","pages":"Article 111422"},"PeriodicalIF":4.4,"publicationDate":"2024-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142280996","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}

{"title":"Exploring m6A methylation in skin Cancer: Insights into molecular mechanisms and treatment","authors":"Mingjun Cai,&nbsp;Xueqing Li,&nbsp;Xueyu Luan,&nbsp;Pengyuan Zhao,&nbsp;Qing Sun","doi":"10.1016/j.cellsig.2024.111420","DOIUrl":"10.1016/j.cellsig.2024.111420","url":null,"abstract":"<div><div>N6-methyladenosine (m6A) is the most common and prevalent internal mRNA modification in eukaryotes. m6A modification is a dynamic and reversible process regulated by methyltransferases, demethylases, and m6A binding proteins. Skin cancers, including melanoma and nonmelanoma skin cancers (NMSCs), are among the most commonly diagnosed cancers worldwide. m6A methylation is involved in the regulation of RNA splicing, translation, degradation, stability, translocation, export, and folding. Aberrant m6A modification participates in the pathophysiological processes of skin cancers and is associated with tumor cell proliferation, invasion, migration, and metastasis during cancer progression. In this review, we provide a comprehensive summary of the biological functions of m6A and the most up-to-date evidence related to m6A RNA modification in skin cancer. We also emphasize the potential clinical applications in the diagnosis and treatment of skin cancers.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"124 ","pages":"Article 111420"},"PeriodicalIF":4.4,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142280994","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}

{"title":"Unraveling the role of the renin-angiotensin system in severe mental illnesses: An insight into psychopathology and cognitive deficits","authors":"Aline Silva de Miranda ,&nbsp;Danielle S. Macedo ,&nbsp;Lia Lira O. Sanders ,&nbsp;Aline S. Monte ,&nbsp;Michelle Verde Ramo Soares ,&nbsp;Antonio Lucio Teixeira","doi":"10.1016/j.cellsig.2024.111429","DOIUrl":"10.1016/j.cellsig.2024.111429","url":null,"abstract":"<div><div>Severe mental illnesses (SMI), especially schizophrenia and bipolar disorder (BD), are associated with significant distress to patients, reduced life expectancy and a higher cost of care. There is growing evidence that SMI may increase the risk of dementia in later life, posing an additional challenge in the management of these patients. SMI present a complex and highly heterogeneous pathophysiology, which has hampered the understanding of its underlying pathological mechanisms and limited the success of the available therapies. Despite the advances in therapeutic approaches in psychiatry over the past decades, treatment resistance is still a common problem in clinical practice, highlighting the urgent need for novel therapeutic targets for SMI. The discovery that renin-angiotensin system (RAS) components are expressed in the central nervous system opened new possibilities for investigating a potential role for this system in the neurobiology of SMI. The safety and efficacy of AT₁ receptor blockers and angiotensin-converting enzyme inhibitors in cardiovascular and metabolic diseases, common medical comorbidities among SMI patients and well-known risk factors for dementia, suggest the potential scalability of these strategies for the management of SMI outcomes including the risk of subsequent dementia. This review aimed to discuss the available evidence from animal models and human studies of the potential involvement of RAS in the pathophysiology of SMI. We also provided a reflection on drawbacks and perspectives that can foster the development of new related therapeutic strategies.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"124 ","pages":"Article 111429"},"PeriodicalIF":4.4,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142281009","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}

{"title":"The renin-angiotensin-aldosterone system: An old tree sprouts new shoots","authors":"Yaqing Ruan ,&nbsp;Yongxin Yu ,&nbsp;Meiqin Wu ,&nbsp;Yulang Jiang ,&nbsp;Yuliang Qiu ,&nbsp;Shiwei Ruan","doi":"10.1016/j.cellsig.2024.111426","DOIUrl":"10.1016/j.cellsig.2024.111426","url":null,"abstract":"<div><div>The intricate physiological and pathological diversity of the Renin-Angiotensin-Aldosterone System (RAAS) underpins its role in maintaining bodily equilibrium. This paper delves into the classical axis (Renin-ACE-Ang II-AT1R axis), the protective arm (ACE2-Ang (1–7)-MasR axis), the prorenin-PRR-MAP kinases ERK1/2 axis, and the Ang IV-AT4R-IRAP cascade of RAAS, examining their functions in both physiological and pathological states. The dysregulation or hyperactivation of RAAS is intricately linked to numerous diseases, including cardiovascular disease (CVD), renal damage, metabolic disease, eye disease, Gastrointestinal disease, nervous system and reproductive system diseases. This paper explores the pathological mechanisms of RAAS in detail, highlighting its significant role in disease progression. Currently, in addition to traditional drugs like ACEI, ARB, and MRA, several novel therapeutics have emerged, such as angiotensin receptor-enkephalinase inhibitors, nonsteroidal mineralocorticoid receptor antagonists, aldosterone synthase inhibitors, aminopeptidase A inhibitors, and angiotensinogen inhibitors. These have shown potential efficacy and application prospects in various clinical trials for related diseases. Through an in-depth analysis of RAAS, this paper aims to provide crucial insights into its complex physiological and pathological mechanisms and offer valuable guidance for developing new therapeutic approaches. This comprehensive discussion is expected to advance the RAAS research field and provide innovative ideas and directions for future clinical treatment strategies.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"124 ","pages":"Article 111426"},"PeriodicalIF":4.4,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142281008","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}

{"title":"NF-κB p105-mediated nuclear translocation of ERK is required for full activation of IFNγ-induced iNOS expression","authors":"Kosuke Zenke,&nbsp;Rino Sugimoto,&nbsp;Sachiko Watanabe,&nbsp;Masashi Muroi","doi":"10.1016/j.cellsig.2024.111424","DOIUrl":"10.1016/j.cellsig.2024.111424","url":null,"abstract":"<div><div>Inducible nitric oxidase (iNOS) encoded by <em>Nos2</em> is a representative IFNγ-inducible effector molecule that plays an important role in both innate and adaptive immunity. In the present study, we demonstrated that full-length NF-κB p105 (p105), which is a precursor of NF-κB p50 (p50), is required for full activation of IFNγ-induced iNOS expression in the RAW264.7 mouse macrophage cell line. In comparison to wild-type (WT) RAW264.7 cells, p105 KO RAW264.7 (p105 KO) cells completely lost IFNγ-induced iNOS expression. Despite the limited effect of exogenous expression of p50 in p105 KO cells on IFNγ-induced <em>Nos2</em> promoter activity, p105 expression fully restored IFNγ-induced <em>Nos2</em> promoter activity to a level comparable to that of WT cells, suggesting an important role for full-length p105 in IFNγ-induced iNOS expression. While the expression and phosphorylation of JAK1 and STAT1 were rather enhanced in p105 KO cells, the phosphorylation of c-Jun downstream of MAPK signaling was decreased. IFNγ-induced phosphorylation of ERK, a kinase for IFNγ-induced c-Jun phosphorylation, was not significantly reduced in p105 KO cells, although the nuclear activity of ERK was significantly decreased due to its reduced translocation to the nucleus. Expression of iNOS, nuclear translocation of ERK, and phosphorylation of c-Jun were restored by stable supplementation of p105 in p105 KO cells. These results suggest that p105 is required for the nuclear translocation of ERK and the subsequent phosphorylation of c-Jun, which are necessary for full activation of IFNγ-induced iNOS expression. Reduced nuclear translocation of ERK in p105 KO cells was also observed in the activation of ERK following serum starvation, further suggesting that the involvement of p105 in ERK nuclear translocation is not limited to IFNγ-stimulated cells but is a more general function of p105.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"124 ","pages":"Article 111424"},"PeriodicalIF":4.4,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142281005","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}

{"title":"Inhibition of ubiquitin-specific protease 7 ameliorates ferroptosis-mediated myocardial infarction by contrasting oxidative stress: An in vitro and in vivo analysis","authors":"Dong Yang ,&nbsp;Tiling Zhang ,&nbsp;Hai Qu,&nbsp;Shaolong Li,&nbsp;Jing Lu,&nbsp;Wanyan Cao,&nbsp;Zhipeng Chen,&nbsp;Han Zhang,&nbsp;Jing Yang,&nbsp;Jin Wang","doi":"10.1016/j.cellsig.2024.111423","DOIUrl":"10.1016/j.cellsig.2024.111423","url":null,"abstract":"<div><h3>Background</h3><p>Our prior research determined that USP7 exacerbates myocardial injury. Additionally, existing studies indicate a strong connection between USP7 and ferroptosis. However, the influence of USP7 on ferroptosis-mediated myocardial infarction (MI) remains unclear. Given these findings, we are particularly interested in USP7's regulatory role in ferroptosis-mediated MI and its underlying mechanisms.</p></div><div><h3>Methods</h3><p>In this study, we established MI models and lentivirus-transfected groups to inhibit USP7 expression both in vivo and in vitro. Cardiac function was detected with Echocardiography. TTC and HE staining were employed to assess myocardial alterations. The expression of ferroptosis markers (PTGS2, ACSL4, GPX4) were analyzed by RT-qPCR and Western blotting. Flow cytometry and ELISA were used for measuring Fe²⁺, lipid ROS, GSH, and GSSG levels. TEM and Prussian blue staining were used to observe mitochondrial alterations and iron deposition. RT-qPCR, Western blotting, and immunofluorescence were conducted to analyze Keap1, Nrf2, and nuclear Nrf2 expression in vitro and in vivo.</p></div><div><h3>Results</h3><p>In the MI model group, USP7 expression significantly increased, worsening ferroptosis-mediated MI. Conversely, in the USP7-inhibited group, activation of the Keap1-Nrf2 signaling pathway improved ferroptosis-mediated MI outcomes. In vitro, the MI model exhibited a marked decline in cardiomyocyte viability and notable mitochondrial damage. However, these issues improved in the USP7-inhibited groups. In vivo, USP7 intensified MI and iron deposition within the MI model group, with decreased values of LVEF, LVFS, SV, LVAWd, and LVPWs, all of which showed improvement in the USP7-inhibited group, except for LVPWd and LVPWs, which showed no significant variation. Importantly, both the in vitro and in vivo experiments revealed analogous results: a reduction in Keap1 expression and an increase in both Nrf2 and nuclear Nrf2 post USP7 inhibition. Additionally, GPX4 expression decreased while PTGS2 and ACSL4 expressions increased. Notably, concentrations of Fe²⁺, lipid ROS, GSH, and GSSG significantly decreased.</p></div><div><h3>Conclusion</h3><p>In vitro and in vivo studies have found that inhibition of USP7 attenuates iron deposition and suppresses oxidative stress, resulting in amelioration of ferroptosis-induced MI.</p></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"124 ","pages":"Article 111423"},"PeriodicalIF":4.4,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142271570","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}

{"title":"Molecular mechanisms of zymosan-induced inflammasome activation in macrophages","authors":"Rangel L. Silva ,&nbsp;Alexandre H. Lopes ,&nbsp;Amanda Becerra ,&nbsp;Miriam M. Fonseca ,&nbsp;Alexandre Maganin ,&nbsp;Andre L.L. Saraiva ,&nbsp;Fernando Q. Cunha ,&nbsp;Jose C. Alves-Filho ,&nbsp;Dario S. Zamboni ,&nbsp;Thiago M. Cunha","doi":"10.1016/j.cellsig.2024.111418","DOIUrl":"10.1016/j.cellsig.2024.111418","url":null,"abstract":"<div><div>Zymosan is a β-glucan-rich component derived from the cell walls of <em>Saccharomyces cerevisiae</em> extensively used in research for its potent immunomodulatory properties. It can prompt inflammatory responses such as peritonitis and arthritis, and is particularly used to study the immune response to fungal particles. Although the zymosan induced-release of the proinflammatory cytokine IL-1β by macrophages is an essential mechanism for combating fungal infection and inducing inflammation, the exact processes leading to its release remain not well understood. In this study, we uncover the intracellular mechanisms involved in zymosan induced-release of active IL-1β by peritoneal macrophages. Zymosan initiates pro-IL-1β formation through TLR2/MyD88 activation; however, Dectin-1 activation only amplify the conversion of pro-IL-1β into its active form. The conversion of inactive to active IL-1β upon zymosan stimulation depends on the NLRP3, ASC, and caspase-1 driven by the decrease in intracellular potassium ions. Notably, zymosan-induced activation of caspase-1 does not require phagocytosis. Instead, zymosan induces a rapid drop in the intracellular ATP concentration, which occurs concomitant with caspase-1 and IL-1β activation. Accordingly, disruption of glycolytic flux during zymosan stimulation promotes an additional reduction of intracellular ATP and concurrently amplifies the activation of caspase-1 and IL-1β. These results reveal that fungal recognition by macrophages results in a metabolic dysfunction, leading to a decrease of intracellular ATP associated with inflammasome activation.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"124 ","pages":"Article 111418"},"PeriodicalIF":4.4,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142280995","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}

{"title":"CircHIPK3 regulates cementoblast differentiation via the miR-10b-5p/DOHH/NF-κB axis","authors":"Gengming Zhang ,&nbsp;Zhendong Tao ,&nbsp;Biao Li ,&nbsp;Jiaqi Zhu ,&nbsp;Lijuan Mo ,&nbsp;Zhengguo Cao ,&nbsp;Mingyuan Du ,&nbsp;Hong He","doi":"10.1016/j.cellsig.2024.111427","DOIUrl":"10.1016/j.cellsig.2024.111427","url":null,"abstract":"<div><h3>Background</h3><div>Intact cementum is vital for tooth stability and health. Cementoblasts, which line the root surface, are responsible for cementum formation. Recent evidence suggests that circular RNAs (circRNAs) are involved in various cellular functions and may have clinical applications. Although circHIPK3 has been shown to participate in osteogenesis, its role in cementoblast differentiation and mineralization is not well understood.</div></div><div><h3>Methods</h3><div>The ring structure of circHIPK3 was confirmed using Sanger sequencing and an actinomycin D assay. Subcellular localization of circHIPK3 was assessed using a nucleus-cytoplasm separation assay. RT-qPCR was employed to analyze circHIPK3 expression during cementoblast differentiation and following TNF-α treatment. <em>In vivo</em>, periapical lesions were induced in mouse mandibular first molars to mimic an inflammatory environment, and circHIPK3 expression was evaluated. The interaction of the circHIPK3/miR-10b-5p/DOHH axis was explored through RNA pull-down assays, bioinformatics analysis, and dual-luciferase reporter assays. The effects on cementoblast differentiation and mineralization were assessed by measuring osteogenic markers, alkaline phosphatase (ALP) activity, ALP staining, and alizarin red S staining.</div></div><div><h3>Results</h3><div>CircHIPK3 was predominantly located in the cytoplasm of cementoblasts, and its expression was significantly upregulated during cementoblast differentiation. Knockdown of circHIPK3 inhibited cementoblast differentiation and mineralization, whereas its overexpression promoted these processes. Mechanistically, circHIPK3 upregulated DOHH expression by sponging miR-10b-5p, thereby enhancing cementoblast differentiation and mineralization. The NF-κB pathway was found to act downstream of the circHIPK3/miR-10b-5p/DOHH axis in these processes. Additionally, circHIPK3 expression was significantly downregulated in inflammatory environments both <em>in vitro</em> and <em>in vivo</em>. Forced overexpression of circHIPK3 mitigated the inhibitory effects of TNF-α on cementoblast differentiation and mineralization.</div></div><div><h3>Conclusion</h3><div>CircHIPK3 acts as a positive regulator of cementoblast differentiation and mineralization through the miR-10b-5p/DOHH/NF-κB axis, playing a crucial role in both normal and pathological cementogenesis.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"124 ","pages":"Article 111427"},"PeriodicalIF":4.4,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142280992","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}

{"title":"TRIB3 knockdown increases the sensitivity of clear cell renal cell carcinoma to sunitinib by inducing ferroptosis","authors":"Zixuan Chen ,&nbsp;Xing Jia ,&nbsp;Zhou Wang ,&nbsp;Yuesong Cai ,&nbsp;An Xu ,&nbsp;Chengtao Han ,&nbsp;Sheng Cheng ,&nbsp;Min Liu","doi":"10.1016/j.cellsig.2024.111421","DOIUrl":"10.1016/j.cellsig.2024.111421","url":null,"abstract":"<div><p>Sunitinib resistance presents a significant challenge in the treatment of clear cell renal cell carcinoma (ccRCC). The role of TRIB3, a newly identified oncogene, in tumor drug resistance has been widely studied. However, the mechanism by which TRIB3 contributes to sunitinib resistance in ccRCC has not been previously explored. This study aimed to investigate the mechanism through which TRIB3 regulates ferroptosis to increase the susceptibility of ccRCC to sunitinib treatment. Bioinformatics analysis and experimental validation revealed that TRIB3 is significantly upregulated in ccRCC tissues and is associated with poor prognosis. Knockdown of TRIB3 using siRNA transfection inhibited the proliferation and migration of ccRCC cells and induced ferroptosis. Following sunitinib treatment, TRIB3 knockdown increased cell sensitivity to sunitinib, enhanced the suppressive impact of sunitinib, and augmented sunitinib-induced ferroptosis. This study demonstrated that TRIB3 knockdown induces ferroptosis by targeting the SLC7A11/GPX4 pathway and enhances therapeutic efficacy of sunitinib for ccRCC, providing new insights and potential strategies to overcome the challenge of sunitinib resistance in ccRCC.</p></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"124 ","pages":"Article 111421"},"PeriodicalIF":4.4,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142271559","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}

{"title":"MEK inhibitor trametinib combined with PI3K/mTOR inhibitor BEZ-235 as an effective strategy against NSCLC through impairment of glucose metabolism","authors":"Yanying Liu ,&nbsp;Binyang Qing ,&nbsp;Weiwei Ke ,&nbsp;Mian Wang","doi":"10.1016/j.cellsig.2024.111415","DOIUrl":"10.1016/j.cellsig.2024.111415","url":null,"abstract":"<div><p>The MAPK and PI3K/AKT/mTOR pathways are aberrantly activated in non-small cell lung cancer (NSCLC) patients, but therapeutic efficacy of NSCLC using trametinib (MEK inhibitor) or BEZ-235 (dual PI3K/mTOR inhibitor) alone is still unsatisfactory. Therefore, in this study, we aimed to determine whether the combination of trametinib with BEZ-235 exerted synergistic effects against NSCLC in both <em>in vitro</em> and <em>in vivo</em> models, and we preliminarily explored the effect of this combination therapy on glucose metabolism. Our results showed that trametinib combined with BEZ-235 could better inhibit cell proliferation and colony formation, induce G0/G1 phase arrest and apoptosis, and suppress cell invasion and migration compared with the single agent. The combination index demonstrated that trametinib and BEZ-235 exerted strong synergistic effects. Additionally, trametinib and BEZ-235 exhibited synergistic antitumor effects <em>in vivo</em>. Furthermore, trametinib and BEZ-235 synergistically downregulated the expression of related proteins in the MAPK and PI3K/AKT/mTOR pathways, and decreased glucose consumption and lactic acid production through suppressing the expressions of glucose transporter 1 (GLUT1) and lactate dehydrogenase A (LDHA). These data imply that simultaneous inhibition of the MAPK and PI3K/AKT/mTOR pathways using trametinib combined with BEZ-235 could synergistically impair glucose metabolism, resulting in an obvious synergistic therapeutic effect against NSCLC.</p></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"124 ","pages":"Article 111415"},"PeriodicalIF":4.4,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142271558","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}