Journal of cellular signaling最新文献

{"title":"Chronic IL-1 Exposed AR+ PCa Cell Lines Show Conserved Loss of IL-1 Sensitivity and Evolve Both Conserved and Unique Differential Gene Expression Profiles","authors":"S. E. Thomas-Jardin, M. Kanchwala, Haley Dahl, Vivian M Liu, Rohan Ahuja, Reshma Soundharrajan, Nicole Roos, Sydney Diep, Amrit Sandhu, Chao Xing, N. Delk","doi":"10.33696/signaling.2.058","DOIUrl":"https://doi.org/10.33696/signaling.2.058","url":null,"abstract":"Introduction: Inflammation drives prostate cancer (PCa) progression. While inflammation is a cancer hallmark, the underlying mechanisms mediating inflammation-induced PCa are still under investigation. Interleukin-1 (IL-1) is an inflammatory cytokine that promotes cancer progression, including PCa metastasis and castration resistance. We previously found that acute IL-1 exposure represses PCa androgen receptor (AR) expression concomitant with the upregulation of pro-survival proteins, causing de novo accumulation of castration-resistant PCa cells. However, acute inflammation is primarily anti-tumorigenic, while chronic inflammation is pro-tumorigenic. Thus, using the LNCaP PCa cell line as model, we found that PCa cells can evolve insensitivity to chronic IL-1 exposure, restoring AR and AR activity and acquiring castration resistance. In this paper we expanded our chronic IL-1 model to include the MDA-PCa-2b PCa cell line to investigate the response to acute versus chronic IL-1 exposure and to compare the gene expression patterns that evolve in the LNCaP and MDA-PCa-2b cells chronically exposed to IL-1. Methods: We chronically exposed MDA-PCa-2b cells to IL-1α or IL-1β for several months to establish sublines. Once established, we determined subline sensitivity to exogenous IL-1 using cell viability assay, RT-qPCR and western blot. RNA sequencing was performed for parental and subline cells and over representation analysis (ORA) for geneset enrichment of biological process/pathway was performed. Results: MDA-PCa-2b cells repress AR and AR activity in response to acute IL-1 exposure and evolve insensitivity to chronic IL-1 exposure. While cell biological and molecular response to acute IL-1 signaling is primarily conserved in LNCaP and MDA-PCa-2b cells, including upregulation of NF-κB signaling and downregulation of cell proliferation, the LNCaP and MDA-PCa-2b cells evolve conserved and unique molecular responses to chronic IL-1 signaling that may promote or support tumor progression. Conclusions: Our chronic IL-1 subline models can be used to identify underlying molecular mechanisms that mediate IL-1-induced PCa progression.","PeriodicalId":73645,"journal":{"name":"Journal of cellular signaling","volume":"2 1","pages":"248 - 260"},"PeriodicalIF":0.0,"publicationDate":"2021-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81328669","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":"Novel Treatments Targeting the Dysregulated Cell Signaling Pathway during Sepsis","authors":"Justin H. Franco, Xiaohuan Chen, Z. Pan","doi":"10.33696/signaling.2.055","DOIUrl":"https://doi.org/10.33696/signaling.2.055","url":null,"abstract":"Previously characterized as a purely immune mediated disease, sepsis is now recognized as a dysregulated multisystem response against a pathogen. Recognition of the infectious agent by pathogen recognition receptors (PRRs) can initiate activation of the NF-κB signaling pathway and promote the secretion of proinflammatory cytokines. During sepsis, the activation of NF-κB is dysregulated and results in cytokine storm, or the pathologic release of cytokines. Current treatments for sepsis rely on broad spectrum antimicrobial medications and fluid replacement therapy, to neutralize the inciting pathogen and maintain adequate blood pressure. The addition of vasopressor therapy is also utilized when sepsis progresses to septic shock, which is defined by treatment resistant hypotension. Even though modern treatment guidelines have improved clinical outcomes, the mortality rate of sepsis and septic shock is still 15–20% and 20–50%, respectively. To reduce mortality, recent sepsis treatment research has focused on investigating novel therapeutics that can attenuate the dysregulated NF-κB signaling pathway. Antioxidants, such as Retinoic acid and Oxytocin, can reduce activation of the NF-κB pathway by neutralizing stimulatory reactive oxygen species (ROS). Likewise, anti-inflammatory agents can also affect the NF-κB pathway by decreasing the secretion of proinflammatory cytokines, such as TNFα and IL-6. Novel anti-inflammatory cytokines, such as IL-37 and IL-38, have recently been characterized and shown to reduce inflammation in mice with bacterial sepsis. Separately, antioxidants and anti-inflammatory cytokines show promise as potential therapies for sepsis, however, a combined therapy including both agents may prove more beneficial in further improving clinical outcomes.","PeriodicalId":73645,"journal":{"name":"Journal of cellular signaling","volume":"4 1","pages":"228 - 234"},"PeriodicalIF":0.0,"publicationDate":"2021-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81019542","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":"SPOCK1: New Mechanistic Insight into Liver Fibrosis","authors":"Zhipeng Du, Yuhui Fan, D. Tian","doi":"10.33696/signaling.2.046","DOIUrl":"https://doi.org/10.33696/signaling.2.046","url":null,"abstract":"Chronic liver diseases with different etiologies can provoke a fibrotic wound-healing response, which leads to liver fibrosis. Liver fibrosis is characterized by abnormal deposition and distribution of extracellular matrix (ECM), which restricts the regeneration of normal liver, and finally results in liver cirrhosis, liver failure or even hepatocellular carcinoma (HCC) [1]. Etiologically, about 40% of HCC is caused by hepatitis B virus (HBV), 40% caused by hepatitis C virus (HCV), 11% caused by chronic alcohol abuse, and about 10% due to other causes, with an increasing prevalence of nonalcoholic fatty liver disease, and all these etiologies could lead to liver fibrosis, and contribute to a favorable niche for tumorgenesis [2]. Globally, liver cirrhosis currently accounts for approximately 1.16 million death each year, which ranks the 11th most common causes of death [2]. Despite increasing development of therapeutic strategies in the past two decades, there is still no approved anti-fibrotic drug to date [3]. Therefore, it is urgent to make further elucidation of the mechanism of liver fibrogenesis.","PeriodicalId":73645,"journal":{"name":"Journal of cellular signaling","volume":"373 ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"72506347","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":"A Brief Update on STAT3 Signaling: Current Challenges and Future Directions in Cancer Treatment","authors":"K. Taniguchi, M. Tsugane, A. Asai","doi":"10.33696/signaling.2.050","DOIUrl":"https://doi.org/10.33696/signaling.2.050","url":null,"abstract":"Due to its importance in a wide range of cellular processes, including cell proliferation, apoptosis, and immune evasion, the signal transducer and activator of transcription (STAT) 3 signaling pathway has been studied intensively over the past few decades. Dysregulation of the STAT3 signaling pathway is closely associated with initiation and development of various types of hematologic or solid malignancies (approximately 70% of those appearing in humans) [1].","PeriodicalId":73645,"journal":{"name":"Journal of cellular signaling","volume":"11 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77974568","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":"Altering CAR Construct Design to Ameliorate CAR-T Cell Therapy Associated Cytokine Release Syndrome","authors":"Zhicheng Du, S. Zha, Y. Ng, Shu Wang","doi":"10.33696/signaling.2.045","DOIUrl":"https://doi.org/10.33696/signaling.2.045","url":null,"abstract":"Cytokine release syndrome represents a significant barrier to the widespread application of chimeric antigen receptor (CAR)-T cell therapies. We performed a broad analysis of preclinical and clinical studies that tested different designs of the CAR construct to tune CAR signaling, with an emphasis on effects of CAR designs on cytokine release from activated CAR-T cells. Evidence from these studies has shown that CAR signal strength and induced cytokine release can be effectively tuned by choosing different antigenbinding domains, hinge and transmembrane regions, costimulatory domains, and activation domains of a CAR construct. The detailed understanding in this aspect will pave the way to develop CAR-T cell products that exert robust anti-cancer function without the exceeding release of cytokines, thus fulfilling their promise in cancer therapy.","PeriodicalId":73645,"journal":{"name":"Journal of cellular signaling","volume":"21 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"91090310","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":"TTK: A Promising Target in Malignant Tumors","authors":"Weiping Yao, Mingyun Jiang, Minjun Zhang, Haibo Zhang, Xiaodong Liang","doi":"10.33696/signaling.2.053","DOIUrl":"https://doi.org/10.33696/signaling.2.053","url":null,"abstract":"TTK, also known as MPS1 (the monopolar spindle 1)/ MPS1L1, is located on chromosome 6q13-q21 and encodes a dual-specific protein kinase that phosphorylates serine and threonine [1]. The spindle assembly checkpoint (SAC) plays a key role in mitosis. The SAC acts as a molecular monitoring mechanism, which delays mitosis until all chromosomes are properly attached to the spindle microtubules. As a key regulator of the SAC, TTK plays an important role in controlling cell cycle progression and maintaining genomic integrity [2]. TTK is vital for the recruitment of kinetochore components to unattached kinetochores and is essential for correcting improperly attached chromosomes. Interestingly, TTK is highly expressed in many types of malignant tumors [3]. However, TTK expression is low in most organs, except in the testis and placenta. Once TTK is inhibited, cancer cells exit mitosis prematurely, with more chromosome segregation errors and aneuploids. After several rounds of cell division, the accumulation of chromosome segregation errors may lead to cancer cell death [4]. Therefore, TTK has gradually become a research hotspot for anticancer drugs, and TTK inhibitors are increasingly being investigated in clinical trials.","PeriodicalId":73645,"journal":{"name":"Journal of cellular signaling","volume":"8 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"91205284","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":"NH2-Terminal Cleavage of Cardiac Troponin I Signals Adaptive Response to Cardiac Stressors","authors":"C. Warren, M. Halas, H. Feng, B. Wolska, Jian-Ping Jin, R. Solaro","doi":"10.33696/signaling.2.048","DOIUrl":"https://doi.org/10.33696/signaling.2.048","url":null,"abstract":"Cardiac sarcomeres express a variant of troponin I (cTnI) that contains a unique N-terminal extension of ~30 amino acids with regulatory phosphorylation sites. The extension is important in the control of myofilament response to Ca2+, which contributes to the neuro-humoral regulation of the dynamics of cardiac contraction and relaxation. Hearts of various species including humans express a stress-induced truncated variant of cardiac troponin I (cTnI-ND) missing the first ~30 amino acids and functionally mimicking the phosphorylated state of cTnI. Studies have demonstrated that upregulation of cTnI-ND potentially represents a homeostatic mechanism as well as an adaptive response in pathophysiology including ischemia/reperfusion injury, beta adrenergic maladaptive activation, and aging. We present evidence showing that cTnI-ND can modify the trigger for hypertrophic cardiomyopathy (HCM) by reducing the Ca2+ sensitivity of myofilaments from hearts with an E180G mutation in α-tropomyosin. Induction of this truncation may represent a therapeutic approach to modifying Ca2+-responses in hearts with hypercontractility or heat failure with preserved ejection fraction.","PeriodicalId":73645,"journal":{"name":"Journal of cellular signaling","volume":"10 1","pages":"162 - 171"},"PeriodicalIF":0.0,"publicationDate":"2021-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81263147","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":"Function of Mitogen-Activated Protein Kinases in Hepatic Inflammation","authors":"Gabrielle Westenberger, Jacob Sellers, Savanie Fernando, S. Junkins, S. Han, Kisuk Min, A. Lawan","doi":"10.33696/signaling.2.049","DOIUrl":"https://doi.org/10.33696/signaling.2.049","url":null,"abstract":"The western diet and overuse of anti-inflammatory medication have caused a great deal of stress on the liver. Obesity and the associated inflammatory state in insulin-responsive tissues result in the release of pro-inflammatory cytokine that activates the stress-responsive MAPKs, p38 MAPK, and JNK. These MAPKs have figured prominently as critical effectors in physiological and pathophysiological hepatic inflammation. In contrast, evidence for a role for ERK1/2 in hepatic inflammation has been less well developed. In this review article, we describe recent insights into the physiology and pathophysiology of the role of stress-responsive MAPKs in hepatic inflammation during obesity and liver injury with a focus on macrophages, hepatocytes and hepatic stellate cells. In response to metabolic stress and liver injury, JNK activation in macrophages and hepatocytes promotes the secretion of inflammatory cytokines and macrophage and neutrophil infiltration. p38 MAPK plays an important role in contributing to the progression of hepatic inflammation in response to various hepatic cellular stresses, although the precise substrates mediating these effects in hepatocytes and hepatic stellate cells remain to be identified. Both JNK and p38 MAPK promotes profibrotic behavior in hepatic stellate cells.","PeriodicalId":73645,"journal":{"name":"Journal of cellular signaling","volume":"29 1","pages":"172 - 180"},"PeriodicalIF":0.0,"publicationDate":"2021-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83501677","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":"APE1/Ref-1 – One Target with Multiple Indications: Emerging Aspects and New Directions","authors":"M. Mijit, R. Caston, S. Gampala, M. Fishel, J. Fehrenbacher, M. Kelley","doi":"10.33696/signaling.2.047","DOIUrl":"https://doi.org/10.33696/signaling.2.047","url":null,"abstract":"In the realm of DNA repair, base excision repair (BER) protein, APE1/Ref-1 (Apurinic/Apyrimidinic Endonuclease 1/Redox Effector - 1, also called APE1) has been studied for decades. However, over the past decade, APE1 has been established as a key player in reduction-oxidation (redox) signaling. In the review by Caston et al. (The multifunctional APE1 DNA repair-redox signaling protein as a drug target in human disease), multiple roles of APE1 in cancer and other diseases are summarized. In this Review, we aim to expand on the contributions of APE1 to various diseases and its effect on disease progression. In the scope of cancer, more recent roles for APE1 have been identified in cancer cell metabolism, as well as chemotherapy-induced peripheral neuropathy (CIPN) and inflammation. Outside of cancer, APE1 signaling may be a critical factor in inflammatory bowel disease (IBD) and is also an emergent area of investigation in retinal ocular diseases. The ability of APE1 to regulate multiple transcription factors (TFs) and therefore multiple pathways that have implications outside of cancer, makes it a particularly unique and enticing target. We discuss APE1 redox inhibitors as a means of studying and potentially combating these diseases. Lastly, we examine the role of APE1 in RNA metabolism. Overall, this article builds on our previous review to elaborate on the roles and conceivable regulation of important pathways by APE1 in multiple diseases.","PeriodicalId":73645,"journal":{"name":"Journal of cellular signaling","volume":"68 1","pages":"151 - 161"},"PeriodicalIF":0.0,"publicationDate":"2021-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"72652074","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":"HGF/MET Signalling and DNA Damage Response: Strategies to Conquer Radiotherapy Resistance in Head and Neck Cancer","authors":"Aaran Vijayakumaran, M. Tavassoli","doi":"10.33696/signaling.2.043","DOIUrl":"https://doi.org/10.33696/signaling.2.043","url":null,"abstract":"Head and neck squamous cell carcinomas (HNSCCs) are a heterogeneous group of aggressive malignancies strongly linked with chronic tobacco exposure, excessive alcohol consumption, and infection with high-risk subtypes of Human Papilloma Virus (HPV). Molecularly, HNSCC is classified into HPV-positive and HPV-negative sub-types [1]. Approximately 600,000 new cases are diagnosed annually with 380,000 deaths worldwide [2]. Despite our increased understanding of the viral and genetic mechanisms underlying HNSCC, the 5-year overall survival rate remains around 50% [3]. Radiotherapy (RT), chemotherapy (CT), surgical eradication, or a combination of all modalities are the current therapeutic options but are highly toxic and cause psychological distress and severely compromised quality of life, and hence associated with both symptomology and treatment survivors of this cancer have the second-highest mortality rate of suicide (63.4 per 100,000; [2000-2014]) [4]. The functional and aesthetic features of the head and neck anatomy are factors that make HNSCCs difficult to treat as tumours are located nearby critical anatomical structures which are sensitive to treatment. Radiotherapy (RT), chemotherapy (CT), surgical eradication, or a combination of all modalities are the current therapeutic options. Cetuximab is a monoclonal antibody (mAb) against the epidermal growth factor receptor (EGFR) and has been the only targeted FDA approved targeted therapy for HNSCC until the recent FDA approval of immunotherapy, but, both Cetuximab and immunotherapy clinical efficacy for HNSCC has been limited [5].","PeriodicalId":73645,"journal":{"name":"Journal of cellular signaling","volume":"85 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83399775","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}