Journal of cellular signaling最新文献

{"title":"Role of Exosomal MicroRNAs in Modulating the Response of Cancer Cells to Paclitaxel Treatment","authors":"Lan Zhao, Cheng Lv, Hui Xie, Xiaoxu Ding","doi":"10.33696/signaling.5.111","DOIUrl":"https://doi.org/10.33696/signaling.5.111","url":null,"abstract":"MicroRNAs (miRNAs) play important roles in gene regulation and have been implicated in various human diseases, including cancer. MiRNAs can be packaged in exosomes and transferred between cells. These exosomal miRNAs regulate intercellular communication and influence almost all aspects of cancer biology, including proliferation, apoptosis, invasion, metastasis, and angiogenesis. Over the last two decades, the association between exosomal miRNAs and paclitaxel resistance has been widely studied. However, the mechanisms underlying the effect of exosomal miRNAs on paclitaxel sensitivity require further research. In this review, we summarize the paclitaxel sensitivity-modulating mechanisms of exosomal miRNAs and discuss exosomal miRNAs as a novel therapeutic tool for paclitaxel resistance.","PeriodicalId":73645,"journal":{"name":"Journal of cellular signaling","volume":"241 ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140274275","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Phorbol-12-Myristate-13-Acetate (PMA) Reactivates Replication from HIV-1 Latency and Induces Jurkat Cell Death","authors":"Xue Wang, Jiangqin Zhao, Indira Hewlett","doi":"10.33696/signaling.5.110","DOIUrl":"https://doi.org/10.33696/signaling.5.110","url":null,"abstract":"HIV-1 has the capability to establish latency during early infection in CD4+ cells, posing a significant challenge to the efforts aimed at curing HIV-1/AIDS. One extensively explored strategy to address this viral latency is the \"shock-and-kill\" approach. This involves reactivating viral replication using latency reversal agents (LRAs) to induce the death of infected cells. Regrettably, no LRAs with proven effectiveness have been identified thus far. In this study, we investigated the impact of Azidothymidine (AZT) treatment interruption and the administration of Phorbol-12-Myristate-13-Acetate (PMA), a PKC activator, as shock-and-kill approaches in vitro. We employed the susceptible Jurkat cell line and utilized a sensitive real-time PCR assay along with Western blotting analysis. Our findings revealed that AZT inhibited HIV-1 replication, and its treatment interruption led to the reactivation of viral replication. This reactivation occurred through the recruitment of host transcription factors, including NFAT, NF-κBp65, Ap-1, and Sp-1. These factors facilitated HIV production via TCR-related pathways, activation of p-TEFb pathways for transcription elongation, and upregulation of Jak/Stat pathways for viral enhancement. Furthermore, we demonstrated that PMA treatment increased the levels of these transcription factors through the activation of TCR-related signaling pathways in HIV-1 infected Jurkat cells, irrespective of the AZT treatment status. PMA also induced cell death through both extrinsic and intrinsic apoptotic signaling pathways, as well as autophagy. These results suggest that PMA effectively employs the shock-and-kill approach in HIV-1 infected Jurkat cells and highlight the potential of PKC pathway activators as promising LRAs.","PeriodicalId":73645,"journal":{"name":"Journal of cellular signaling","volume":"13 11","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140277928","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Teaching an Old Drug a New Trick: Targeting Treatment Resistance in Genitourinary Cancers.","authors":"Karina Aguilar, Anuj K Sharma, Tianyu Yang, Dipen Mehta, Chandramukhi S Panda, Vinata B Lokeshwar","doi":"10.33696/signaling.5.112","DOIUrl":"10.33696/signaling.5.112","url":null,"abstract":"<p><p>In the quest for improving the clinical outcome of patients with metastatic genitourinary cancers, including metastatic renal cell carcinoma (mRCC), the emphasis often is on finding new targeted therapies. However, two studies by Jordan <i>et al. (Oncogenesis 2020)</i> and Wang <i>et al. (Cancer Cell Int 2022)</i> demonstrate the feasibility of improving the efficacy of a modestly effective drug Sorafenib against mRCC by attacking a mechanism hijacked by RCC cells for inactivating Sorafenib. The studies also identified hyaluronic acid synthase -3 (HAS3) as a bonafide target of Sorafenib in RCC cells. The studies demonstrate that an over-the-counter drug Hymecromone (4-methylumbelliferone) blocks inactivation of Sorafenib in RCC cells and improves its efficacy against mRCC through the inhibition of HAS3 expression and HA signaling. In the broader context, improving the efficacy of \"old and failed drugs\" that have favorable safety profiles should increase the availability of effective treatments for patients with advanced cancers.</p>","PeriodicalId":73645,"journal":{"name":"Journal of cellular signaling","volume":"5 2","pages":"51-56"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11081427/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140900515","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Linking Phosphoinositides to Proteins: A Novel Signaling PIPeline.","authors":"Noah D Carrillo, Poorwa Awasthi, Jeong Hyo Lee, Tianmu Wen, Mo Chen, Colin Sterling, Trevor J Wolfe, Vincent L Cryns, Richard A Anderson","doi":"10.33696/signaling.5.118","DOIUrl":"10.33696/signaling.5.118","url":null,"abstract":"<p><p>Phosphoinositide (PIP_n) signaling plays pivotal roles in myriad biological processes and is altered in many diseases including cancer. Canonical PIP_n signaling involves membrane-associated PIP_n lipid second messengers that modulate protein recruitment and activity at membrane focal points. In the nucleus, PIP_n signaling operates separately from membranous compartments defining the paradigm of non-canonical PIP_n signaling. However, the mechanisms by which this non-membranous nuclear PIP_n pool is established and mediates stress signaling is poorly understood. The recent discovery of a p53-signalosome by <i>Chen et al. (Nature Cell Biology 2022)</i> represents a new PIP_n signaling axis that operates independently from membrane structures where PIP_ns are dynamically linked to nuclear p53 and modified by PIP_n kinases and phosphatases, allowing the activation of a nuclear PI 3-kinase/Akt pathway that is entirely distinct from the canonical membrane-localized pathway. Here, we will discuss emerging insights about the non-canonical PIP_n pathway, which links PIP_ns to a growing number of cellular targets and highlight the similarities/differences with its canonical counterpart. We will also discuss potential therapeutic targets in this non-canonical PIP_n pathway, which is likely to be deregulated in many diseases.</p>","PeriodicalId":73645,"journal":{"name":"Journal of cellular signaling","volume":"5 3","pages":"114-121"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11584056/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142712052","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Combating PDAC Drug Resistance: The Role of Ref-1 Inhibitors in Accelerating Progress in Pancreatic Cancer Research.","authors":"Eyram K Kpenu, Mark R Kelley","doi":"10.33696/signaling.5.126","DOIUrl":"10.33696/signaling.5.126","url":null,"abstract":"<p><p>Pancreatic Ductal Adenocarcinoma (PDAC) remains one of the most lethal solid tumor diagnoses given its limited treatment options and dismal prognosis. Its complex tumor microenvironment (TME), heterogeneity, and high propensity for drug resistance are major obstacles in developing effective therapies. Here, we highlight the critical role of Redox effector 1 (Ref-1) in PDAC progression and drug resistance, focusing on its redox regulation of key transcription factors (TFs) such as STAT3, HIF1α, and NF-κB, which are pivotal for tumor survival, proliferation, and immune evasion. We discuss the development of novel Ref-1 inhibitors, including second-generation compounds with enhanced potency and improved pharmacokinetic profiles, which have shown significant promise in preclinical models. These inhibitors disrupt Ref-1's redox function, leading to decreased TF activity and increased chemosensitivity in PDAC cells. We further detail our utilization of advanced preclinical models, such as 3D spheroids, organoids, and Tumor-Microenvironment-on-Chip (T-MOC) systems, which better simulate the complex conditions of the PDAC TME and improve the predictive power of therapeutic responses. By targeting Ref-1 and its associated pathways, in conjunction with improved models, more replicative of PDAC's TME, we are focused on approaches which hold the potential to overcome current therapeutic limitations and advance the development of more effective treatments for PDAC. Our findings suggest that integrating Ref-1 inhibitors into combination therapies could disrupt multiple survival mechanisms within the tumor, offering new hope for improving outcomes in this challenging cancer.</p>","PeriodicalId":73645,"journal":{"name":"Journal of cellular signaling","volume":"5 4","pages":"208-216"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11616473/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142782020","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Navigating the Adipocyte Precursor Niche: Cell-Cell Interactions, Regulatory Mechanisms and Implications for Adipose Tissue Homeostasis.","authors":"Devesh Kesharwani, Aaron C Brown","doi":"10.33696/signaling.5.114","DOIUrl":"10.33696/signaling.5.114","url":null,"abstract":"<p><p>Support for stem cell self-renewal and differentiation hinges upon the intricate microenvironment termed the stem cell 'niche'. Within the adipose tissue stem cell niche, diverse cell types, such as endothelial cells, immune cells, mural cells, and adipocytes, intricately regulate the function of adipocyte precursors. These interactions, whether direct or indirect, play a pivotal role in governing the balance between self-renewal and differentiation of adipocyte precursors into adipocytes. The mechanisms orchestrating the maintenance and coordination of this niche are still in the early stages of comprehension, despite their crucial role in regulating adipose tissue homeostasis. The complexity of understanding adipocyte precursor renewal and differentiation is amplified due to the challenges posed by the absence of suitable surface receptors for identification, limitations in creating optimal <i>ex vivo</i> culture conditions for expansion and constraints in conducting <i>in vivo</i> studies. This review delves into the current landscape of knowledge surrounding adipocyte precursors within the adipose stem cell niche. We will review the identification of adipocyte precursors, the cell-cell interactions they engage in, the factors influencing their renewal and commitment toward adipocytes and the transformations they undergo during instances of obesity.</p>","PeriodicalId":73645,"journal":{"name":"Journal of cellular signaling","volume":"5 2","pages":"65-86"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11141760/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141198541","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ALK1 Signaling in Human Cardiac Progenitor Cells Promotes a Pro-angiogenic Secretome.","authors":"Michayla Moore, Sergey Ryzhov, Douglas B Sawyer, Carlos Gartner, Calvin P H Vary","doi":"10.33696/signaling.5.119","DOIUrl":"10.33696/signaling.5.119","url":null,"abstract":"<p><p>Pro-angiogenic paracrine/autocrine signaling impacts myocardial repair in cell-based therapies. Activin A receptor-like type 1 (<i>ACVRL1</i>, ALK1) signaling plays a pivotal role in cardiovascular development and maintenance, but its importance in human-derived therapeutic cardiac cells is not well understood. Here, we isolated a subpopulation of human highly proliferative cells (hHiPCs) from adult epicardial tissue and found that they express ALK1, a high affinity receptor for bone morphogenetic protein-9 (BMP9), which signals via SMAD1/5 to regulate paracrine/autocrine signaling and angiogenesis. We show that in humans, circulating BMP9 level is negatively associated with the number of epicardial hHiPC and positively associated with endothelial cell (EC) number in the adult heart, implicating the potential importance of this signaling pathway in cardiac cell fate and vascular maintenance. To investigate BMP9/ALK1 signaling in hHiPCs, we selected a primary cell population of hHiPC from each of 3 individuals and studied their responses to BMP9 and BMP10 treatment <i>in vitro</i>. Proteins were collected in conditioned media (CM) for mass spectrometry and cell-based assays on human ECs and hHiPCs. Proteomic analysis of the hHiPC secretome following BMP9 or BMP10 treatment demonstrates that the secreted proteins, sclerostin (SOST), meflin/immunoglobulin superfamily containing leucine rich repeat (ISLR), and insulin-like growth factor binding protein-3 (IGFBP3), are novel regulated targets of BMP9/ALK1 signaling. Lentiviral shRNA and pharmacological inhibition of ALK1 in hHiPCs suppressed transcription and secretion of SOST, ISLR, and IGFBP3 following BMP9 treatment. Moreover, the BMP9-treated secretome of hHiPC increased capillary-like tube formation of ECs and hHiPCs. Treatment of hHiPCs with recombinant SOST increased <i>VEGF-a</i> expression, increased tube formation and enhanced expression of EC receptor marker annexin A2 (ANXA2). These data provide the first proteomic characterization of hHiPC, identifying BMP9/ALK1-mediated target protein secretion in hHiPCs, and underscore the complex role of BMP9/ALK1 signaling in paracrine/autocrine mediated angiogenesis. Data are available via ProteomeXchange with identifier PXD055302.</p>","PeriodicalId":73645,"journal":{"name":"Journal of cellular signaling","volume":"5 3","pages":"122-142"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11488643/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142482422","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Retinoic Acid Induced Cell Signaling as a Counter Against Disease","authors":"Justin H. Franco, Zhixing K. Pan","doi":"10.33696/signaling.4.106","DOIUrl":"https://doi.org/10.33696/signaling.4.106","url":null,"abstract":"Many disease processes result from disruption of physiologic cell signaling pathways. Cancer often develops from the loss of cell cycle regulation, while inflammatory disease results from dysregulated immune activity. Likewise, many microbial infections avoid immune clearance by interfering with cellular antimicrobial pathways. Retinoic Acid (RA) is a dynamic compound, derived from vitamin A, that can regulate various signaling pathways. RA induced cell signaling has proven beneficial against different diseases, such as Acute Promyelocytic Leukemia (APL) and psoriasis. Against APL, RA induces cellular differentiation in cancer cells to restore proper function. In psoriasis, RA downregulates inflammatory pathways, such as NF-κB. RA’s anti-inflammatory properties have also been examined in the context of sepsis, where recent animal studies have shown positive benefits. Along with regulating inflammation, RA exhibits indirect antimicrobial properties. Unlike conventional antimicrobials which target pathogens directly, RA functions as a host-directed therapy (HDT), promoting cell antimicrobial defenses. Recent studies examining RA have shown that it can improve macrophage clearance of microbial pathogens and stimulate the antiviral type-I interferon (IFN) response. RA’s effectiveness has been demonstrated against clinically relevant pathogens, such as Mycobacterium tuberculosis, Aspergillus fumigatus, and Measles virus. In this review, the therapeutic potential of RA to treat various diseases by regulating cell signaling pathways will be explored.","PeriodicalId":73645,"journal":{"name":"Journal of cellular signaling","volume":"108 24","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135138133","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"DIS3L2: Unveiling a New Player in Tumorigenesis, with a Key Role in Colorectal Cancer","authors":"Juan F. García-Moreno, Paulo Matos, Luísa Romão","doi":"10.33696/signaling.4.104","DOIUrl":"https://doi.org/10.33696/signaling.4.104","url":null,"abstract":"DIS3L2 is a 3’-5’ exoribonuclease that recognizes and degrades uridylated transcripts in an exosome-independent manner and participates in several RNA degradation pathways, such as the nonsense-mediated mRNA decay, or the surveillance of aberrant structured non-coding RNAs. Although some studies have linked DIS3L2 to tumorigenesis and cancer-related processes, its exact role in the development and progression of cancer has remained unclear since the discovery of DIS3L2's ribonuclease activity a decade ago. While some authors have reported evidence of a tumor suppressor role for this exoribonuclease, other studies have shown DIS3L2 as a driver of tumorigenesis. Although differences in tissue type and methodologic approaches may somewhat account for the opposing findings, a recent study from our group further supports a pro-tumorigenic role for DIS3L2, this time in promoting colorectal cancer (CRC) progression. Indeed, proper DIS3L2 expression was proven essential to maintain key tumorigenic properties in CRC cells, including cell proliferation and invasion. Here, we summarize the current state of knowledge regarding the impact of DIS3L2 in cancer, namely in colorectal cancer. The collected data unveils DIS3L2 as a novel putative therapeutic target in cancer that warrants further investigation.","PeriodicalId":73645,"journal":{"name":"Journal of cellular signaling","volume":"35 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135273263","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Depleting Cellular Retinoic Acid Binding Protein 1 Impairs UPRmt","authors":"Chin-Wen Wei, Thomas Lerdall, Fatimah Najjar, Li-Na Wei","doi":"10.33696/signaling.4.102","DOIUrl":"https://doi.org/10.33696/signaling.4.102","url":null,"abstract":"Mitochondrial dysfunction underlines neurodegenerative diseases which are mostly characterized by progressive degeneration of neurons. We previously reported that Cellular retinoic acid Binding protein 1 (Crabp1) knockout (CKO) mice spontaneously developed age-dependent motor degeneration, with defects accumulated in spinal motor neurons (MNs), the only cell type in spinal cord that expresses CRABP1. Here we uncovered that mitochondrial DNA (mtDNA) content and the expression of genes involved in respiration were significantly reduced in CKO mouse spinal cord, accompanied by significantly elevated reactive oxygen species (ROS) and unfolded protein load, indicating that CRABP1 deficiency caused mitochondrial dysfunction. Further analyses of spinal cord tissues revealed significant reduction in the expression and activity of superoxide dismutase 2 (SOD2), as well as defected mitochondrial unfolded protein response (UPRmt) pathway, specifically an increase in ATF5 mRNA but not its protein level, which suggested failure in the translational response of ATF5 in CKO. Consistently, eukaryotic initiation factor-2α, (eIF2α) phosphorylation was reduced in CKO spinal cord. In a CRABP1 knockdown MN1 model, siCrabp1-MN1, we validated the cell-autonomous function of CRABP1 in modulating the execution of UPRmt. This study reveals a new functional role for CRABP1 in the execution of mitochondrial stress response, that CRABP1 modulates eIF2α phosphorylation thereby contributing to ATF5 translational response that is needed to mitigate mitochondria stress.","PeriodicalId":73645,"journal":{"name":"Journal of cellular signaling","volume":"21 11-12","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135267061","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}