Cellular signalling最新文献

{"title":"The role of cystathionine β-synthase in cancer","authors":"","doi":"10.1016/j.cellsig.2024.111406","DOIUrl":"10.1016/j.cellsig.2024.111406","url":null,"abstract":"<div><p>Cystathionine β-synthase (CBS) occupies a key position as the initiating and rate-limiting enzyme in the sulfur transfer pathway and plays a vital role in health and disease. CBS is responsible for regulating the metabolism of cysteine, the precursor of glutathione (GSH), an important antioxidant in the body. Additionally, CBS is one of the three enzymes that produce hydrogen sulfide (H₂S) in mammals through a variety of mechanisms. The dysregulation of CBS expression in cancer cells affects H₂S production through direct or indirect pathways, thereby influencing cancer growth and metastasis by inducing angiogenesis, facilitating proliferation, migration, and invasion, modulating cellular energy metabolism, promoting cell cycle progression, and inhibiting apoptosis. It is noteworthy that CBS expression exhibits complex changes in different cancer models. In this paper, we focus on the CBS synthesis and metabolism, tissue distribution, potential mechanisms influencing tumor growth, and relevant signaling pathways. We also discuss the impact of pharmacological CBS inhibitors and silencing CBS in preclinical cancer models, supporting their potential as targeted cancer therapies.</p></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142271567","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":"Implications of β-Arrestin biased signaling by angiotensin II type 1 receptor for cardiovascular drug discovery and therapeutics","authors":"","doi":"10.1016/j.cellsig.2024.111410","DOIUrl":"10.1016/j.cellsig.2024.111410","url":null,"abstract":"<div><p>Angiotensin II receptors, Type 1 (AT1R) and Type 2 (AT2R) are 7TM receptors that play critical roles in both the physiological and pathophysiological regulation of the cardiovascular system. While AT1R blockers (ARBs) have proven beneficial in managing cardiac, vascular and renal maladies they cannot completely halt and reverse the progression of pathologies. Numerous experimental and animal studies have demonstrated that β-arrestin biased AT1R-ligands (such as SII-AngII, S1I8, TRV023, and TRV027) offer cardiovascular benefits by blocking the G protein signaling while retaining the β-arrestin signaling. However, these ligands failed to show improvement in heart-failure outcome over the placebo in a phase IIb clinical trial. One major limitation of current β-arrestin biased AT1R-ligands is that they are peptides with short half-lives, limiting their long-term efficacy in patients. Additionally, β-arrestin biased AT1R-ligand peptides, may inadvertently block AT2R, a promiscuous receptor, potentially negating its beneficial effects in post-myocardial infarction (MI) patients. Therefore, developing a small molecule β-arrestin biased AT1R-ligand with a longer half-life and specificity to AT1R could be more effective in treating heart failure. This approach has the potential to revolutionize the treatment of cardiovascular diseases by offering more sustained and targeted therapeutic effects.</p></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0898656824003784/pdfft?md5=0677b80d32693f45f7b1c9a45add5968&pid=1-s2.0-S0898656824003784-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142239322","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}

{"title":"CircJPH1 regulates the NF-κB/HERC5 axis to promote the malignant progression of esophageal squamous cell carcinoma through binding to XRCC6","authors":"","doi":"10.1016/j.cellsig.2024.111403","DOIUrl":"10.1016/j.cellsig.2024.111403","url":null,"abstract":"<div><p>Esophageal squamous cell carcinoma (ESCC) is a prevalent and malignant cancer with an unknown pathogenesis and a poor prognosis; therefore, the identification of effective biomarkers and targets is crucial for its diagnosis and treatment. Circular (circ)RNAs are prominent functional biomarkers and therapeutic targets in various diseases, particularly cancer, due to their widespread expression and regulatory mechanisms. Our study aimed to investigate the therapeutic potential of circRNA for ESCC. We identified Hsa_circ_0137111 for the first time as one of the most significantly up-regulated genes in ESCC sequencing and named it circJPH1. The results of the present study demonstrated an enhanced expression of circJPH1 in ESCC tissues. Moreover, circJPH1-knockdown could significantly inhibit the proliferation, migration, and invasion of ESCC cells, while its overexpression promoted these characteristics. In addition, circJPH1 promoted ESCC cell tumor growth <em>in vivo.</em> For the first time, mass spectrometry and RNA pull-down analysis revealed the interaction of X-ray repair cross-complementary 6 (XRCC6) protein with circJPH1, thereby promoting its nuclear translocation. Consequently, the nuclear factor kappa-B (NF-κB) signaling pathway was activated, leading to an up-regulation of HECT and RLD domain containing E3 ubiquitin protein ligase 5 (HERC5), thereby promoting ESCC progression. In summary, the present study elucidated the regulatory impact of circJPH1 on ESCC progression <em>in vitro</em> and <em>in vivo</em>, thereby indicating its potential role in ESCC treatment.</p></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0898656824003711/pdfft?md5=52628485b0c1f0d8e3df3ae391bd503c&pid=1-s2.0-S0898656824003711-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142172501","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}

{"title":"ALOX5 induces EMT and promotes cell metastasis via the LTB4/BLT2/PI3K/AKT pathway in ovarian cancer","authors":"","doi":"10.1016/j.cellsig.2024.111404","DOIUrl":"10.1016/j.cellsig.2024.111404","url":null,"abstract":"<div><p>Ovarian cancer represents the most lethal gynecological malignancy with high invasiveness. Epithelial-to-mesenchymal transition (EMT) plays a critical role in cancer metastasis. However, the role of ALOX5 in EMT and cancer metastasis in ovarian cancer (OC) remain unclear. In this study, ALOX5 was significantly upregulated in tumorous and metastatic tissue compared with normal tissue. Furthermore, we found that overexpression of ALOX5 promoted cell migration and invasion, while silencing of ALOX5 suppressed migration and invasion in OC cell lines. Mechanistically, we found that enhanced expression of ALOX5 promoted EMT and cancer metastasis through activation of the PI3K/AKT pathway, whereas SNAIl inhibited the transcription of CDH1 in OC cells. Taken together, our results highlight a role for the ALOX5/PI3K/AKT/ SNAI1 axis in OC, which provides novel strategies for the prevention of metastasis in OC.</p></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142173042","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":"SARS-CoV-2 NSP16 promotes IL-6 production by regulating the stabilization of HIF-1α","authors":"","doi":"10.1016/j.cellsig.2024.111387","DOIUrl":"10.1016/j.cellsig.2024.111387","url":null,"abstract":"<div><p>Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the etiologic agent of coronavirus disease 2019 (COVID-19). Severe and fatal COVID-19 cases often display cytokine storm i.e. significant elevation of pro-inflammatory cytokines and acute respiratory distress syndrome (ARDS) with systemic hypoxia. Understanding the mechanisms of these pathogenic manifestations would be essential for the prevention and especially treatment of COVID-19 patients. Here, using a dual luciferase reporter assay for hypoxia-response element (HRE), we initially identified SARS-CoV-2 nonstructural protein 5 (NSP5), NSP16, and open reading frame 3a (ORF3a) to upregulate hypoxia-inducible factor-1α (HIF-1α) signaling. Further experiments showed NSP16 to have the most prominent effect on HIF-1α, thus contributing to the induction of COVID-19 associated pro-inflammatory response. We demonstrate that NSP16 interrupts von Hippel-Lindau (VHL) protein interaction with HIF-1α, thereby inhibiting ubiquitin-dependent degradation of HIF-1α and allowing it to bind HRE region in the IL-6 promoter region. Taken together, the findings imply that SARS-CoV-2 NSP16 induces HIF-1α expression, which in turn exacerbates the production of IL-6.</p></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0898656824003553/pdfft?md5=3bee8dc53ad56d0a6db7e6227015912d&pid=1-s2.0-S0898656824003553-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142173043","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}

{"title":"Mitogen-activated protein kinase signalling in rat hearts during postnatal development: MAPKs, MAP3Ks, MAP4Ks and DUSPs","authors":"","doi":"10.1016/j.cellsig.2024.111397","DOIUrl":"10.1016/j.cellsig.2024.111397","url":null,"abstract":"<div><p>Mammalian cardiomyocytes become terminally-differentiated during the perinatal period. In rodents, cytokinesis ceases after a final division cycle immediately after birth. Nuclear division continues and most cardiomyocytes become binucleated by ∼11 days. Subsequent growth results from an increase in cardiomyocyte size. The mechanisms involved remain under investigation. Mitogen-activated protein kinases (MAPKs) regulate cell growth/death: extracellular signal-regulated kinases 1/2 (ERK1/2) promote proliferation, whilst c-Jun N-terminal kinases (JNKs) and p38-MAPKs respond to cellular stresses. We assessed their regulation in rat hearts during postnatal development (2, 7, 14, and 28 days, 12 weeks) during which time there was rapid, substantial downregulation of mitosis/cytokinesis genes (<em>Cenpa/e/f, Aurkb</em>, <em>Anln</em>, <em>Cdca8</em>, <em>Orc6</em>) with lesser downregulation of DNA replication genes (<em>Orcs1–5</em>, <em>Mcms2–7</em>). MAPK activation was assessed by immunoblotting for total and phosphorylated (activated) kinases. Total ERK1/2 was downregulated, but not JNKs or p38-MAPKs, whilst phosphorylation of all MAPKs increased relative to total protein albeit transiently for JNKs. These profiles differed from activation of Akt (also involved in cardiomyocyte growth). Dual-specificity phosphatases, upstream MAPK kinase kinases (MAP3Ks), and MAP3K kinases (MAP4Ks) identified in neonatal rat cardiomyocytes by RNASeq were differentially regulated during postnatal cardiac development. The MAP3Ks that we could assess by immunoblotting (RAF kinases and Map3k3) showed greater downregulation of the protein than mRNA. MAP3K2/MAP3K3/MAP4K5 were upregulated in human failing heart samples and may be part of the “foetal gene programme” of re-expressed genes in disease. Thus, MAPKs, along with kinases and phosphatases that regulate them, potentially play a significant role in postnatal remodelling of the heart.</p></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0898656824003656/pdfft?md5=eed5b6074e0af991b13170418e8eaf52&pid=1-s2.0-S0898656824003656-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142168492","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}

{"title":"Small molecules targeting mitochondria as an innovative approach to cancer therapy","authors":"","doi":"10.1016/j.cellsig.2024.111396","DOIUrl":"10.1016/j.cellsig.2024.111396","url":null,"abstract":"<div><p>Cellular death evasion is a defining characteristic of human malignancies and a significant contributor to therapeutic inefficacy. As a result of oncogenic inhibition of cell death mechanisms, established therapeutic regimens seems to be ineffective. Mitochondria serve as the cellular powerhouses, but they also function as repositories of self-destructive weaponry. Changes in the structure and activities of mitochondria have been consistently documented in cancer cells. In recent years, there has been an increasing focus on using mitochondria as a targeted approach for treating cancer. Considerable attention has been devoted to the development of delivery systems that selectively aim to deliver small molecules called “mitocans” to mitochondria, with the ultimate goal of modulating the physiology of cancer cells. This review summarizes the rationale and mechanism of mitochondrial targeting with small molecules in the treatment of cancer, and their impact on the mitochondria. This paper provides a concise overview of the reasoning and mechanism behind directing treatment towards mitochondria in cancer therapy, with a particular focus on targeting using small molecules. This review also examines diverse small molecule types within each category as potential therapeutic agents for cancer.</p></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142232820","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":"LncRNA HOXA11-AS intercepts the POU2F2-mediated downregulation of SLC3A2 in osteoarthritis to suppress ferroptosis","authors":"","doi":"10.1016/j.cellsig.2024.111399","DOIUrl":"10.1016/j.cellsig.2024.111399","url":null,"abstract":"<div><h3>Background</h3><p>Osteoarthritis (OA) is a prevalent ailment characterized by the gradual degradation of joints, resulting in discomfort and restricted movement. The recently proposed mechanism of ferroptosis is intricately associated with the initiation and progression of OA. Our study found that the long non-coding RNA HOXA11-AS reduces ferroptosis by increasing the expression of SLC3A2 through the transcription factor POU2F2.</p></div><div><h3>Materials and methods</h3><p>HOXA11-AS was identified through lncRNA microarray analysis, and its impact on chondrocytes and extracellular matrix was assessed using real-time quantitative PCR, western blotting, and CCK8 assays. Subsequently, overexpression of HOXA11-AS in the knee joints of mice confirmed its protective efficacy on chondrocyte phenotype in the OA model. The involvement of HOXA11-AS in regulating ferroptosis via SLC3A2 was further validated through RNA sequencing analysis of mouse cartilage and the assessment of malondialdehyde levels and glutathione peroxidase activity. Finally, a combination of RNA sequencing, pull-down assays, mass spectrometry (MS), and chromatin immunoprecipitation (ChIP) techniques was employed to identify POU2F2 as the crucial transcription factor responsible for repressing the expression of SLC3A2, which can be effectively inhibited by HOXA11-AS.</p></div><div><h3>Results</h3><p>Our study demonstrated that HOXA11-AS effectively enhanced the metabolic homeostasis of chondrocytes, and alleviated the progression of OA in vitro and in vivo experiments. Furthermore, HOXA11-AS was found to enhance SLC3A2 expression, a key regulator of ferroptosis, by interacting with the transcriptional repressor POU2F2.</p></div><div><h3>Conclusions</h3><p>HOXA11-AS promotes SLC3A2 expression and inhibits chondrocyte ferroptosis, by binding to the transcriptional repressor POU2F2, offering a promising and innovative therapeutic approach for OA.</p></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142168495","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":"mTOR potentiates senescent phenotypes and primary cilia formation after cisplatin-induced G2 arrest in retinal pigment epithelial cells","authors":"","doi":"10.1016/j.cellsig.2024.111402","DOIUrl":"10.1016/j.cellsig.2024.111402","url":null,"abstract":"<div><p>Cisplatin, a platinum-based anticancer drug, is used to treat several types of cancer. Despite its effectiveness, cisplatin-induced side effects have often been reported. Although cisplatin-induced toxicities, such as apoptosis and/or necrosis, have been well studied, the fate of cells after exposure to sublethal doses of cisplatin needs further elucidation. Treatment with a sublethal dose of cisplatin induced cell cycle arrest at the G2 phase in retinal pigment epithelial cells. Following cisplatin withdrawal, the cells irreversibly exited the cell cycle and became senescent. Notably, the progression from the G2 to the G1 phase occurred without mitotic entry, a phenomenon referred to as mitotic bypass, resulting in the accumulation of cells containing 4N DNA content. Cisplatin-exposed cells exhibited morphological changes associated with senescence, including an enlarged size of cell and nucleus and increased granularity. In addition, the senescent cells possessed primary cilia and persistent DNA lesions. Senescence induced by transient exposure to cisplatin involves mTOR activation. Although transient co-exposure with an mTORC1 inhibitor rapamycin did not prevent mitotic bypass and entry into senescence, it delayed the progression of senescence and attenuated senescent phenotypes, resulting in shorter primary cilia formation. Conclusively, cisplatin induces senescence in retinal pigment epithelial cells by promoting mTOR activation.</p></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S089865682400370X/pdfft?md5=d45190ff7d660909042fd3d885037e81&pid=1-s2.0-S089865682400370X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142168494","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}

{"title":"HDAC5 deacetylates c-Myc and facilitates cell cycle progression in hepatocellular carcinoma cells","authors":"","doi":"10.1016/j.cellsig.2024.111386","DOIUrl":"10.1016/j.cellsig.2024.111386","url":null,"abstract":"<div><p>Histone deacetylase 5 (HDAC5) is an enzyme that deacetylates lysine residues on the N-terminal of histones and other proteins. It has been reported that HDAC5 deacetylates p53, the critical factor regulating cell cycle, in response to cellular stress, but the transcriptional products haven't been identified. Herein, we used p53 signaling pathway qPCR–chip to determine how HDAC5-mediated deacetylation of p53 affects cell cycle. However, validation using immunoblotting analysis revealed that acetylation of p53 at K120 impacted little to the expression of the genes identified using the qPCR–chip, indicating HDAC5 might deacetylate some other proteins to facilitate cell cycle via transactivating the differentially expressed genes determined by the qPCR–chip. The subsequent assays demonstrated that HDAC5 deacetylated c-Myc at K143 and K157 to facilitate the transactivation of <em>CDK1, CDK4</em>, and <em>CDC25C</em>, promoting cell cycle progression of hepatocellular carcinoma (HCC). This study shows that HDAC5 plays important roles in modulating deacetylation of c-Myc and regulating cell cycle progression, and it proves that LMK-235, the inhibitor targeting HDAC5 potentially serves as a drug for combating HCC via promoting acetylation of c-Myc at K143 and K157.</p></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142145227","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}