{"title":"Norepinephrine mediates adrenergic receptor transcription and oncogenic gene expression in pancreatic ductal adenocarcinoma","authors":"Henry H. Brak, Noelle R.J. Thielman","doi":"10.1016/j.jbior.2025.101097","DOIUrl":"10.1016/j.jbior.2025.101097","url":null,"abstract":"<div><div>Adrenergic stimulation of β<sub>2</sub> receptors has shown to increase pancreatic ductal adenocarcinoma (PDAC) proliferation and migration in an <em>in vitro</em> setting; however, the role of α<sub>1</sub> receptors in these adrenergic signaling pathways is unclear. Previous research has suggested that the MAPK signaling pathway is upregulated in response to β-adrenergic signaling, but other signaling pathways and downstream targets of mutant KRAS have yet to be investigated. This study investigates the role of adrenergic signaling through α<sub>1</sub> and β-receptors in two human-derived PDAC cell lines, examining proliferation, wound healing, and protein expression after treatment with norepinephrine (NE) and in the presence of β and α<sub>1</sub>-receptor antagonism. Using RT-qPCR, the expression of adrenergic receptors and downstream KRAS effector proteins was evaluated. We found that NE has varying effects on proliferation and wound healing in different PDAC cell lines. Moreover, adrenergic receptor expression is under negative feedback control through α<sub>1</sub> signaling in both cell lines. Furthermore, NE decreases expression of MMP9 while also affecting expression of VIM, CCND1, mTOR, and rhoA. We demonstrate genotype dependent effects of adrenergic stimulation on downstream molecular signaling pathways in PDAC that are important for oncogenicity. Based on our findings, genotypic characterization of cell signaling pathways in PDAC may aid further research in effective therapeutics for PDAC.</div></div>","PeriodicalId":7214,"journal":{"name":"Advances in biological regulation","volume":"97 ","pages":"Article 101097"},"PeriodicalIF":0.0,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143927731","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}
Nayila Abulimiti , Rongzhuo Long , Yin He , Junze Dong , Xiaosheng Wang
{"title":"Solid pancancer analysis reveals immune and hematopoietic stem cell and DNA damage repair signatures to distinguish different cancer subtypes","authors":"Nayila Abulimiti , Rongzhuo Long , Yin He , Junze Dong , Xiaosheng Wang","doi":"10.1016/j.jbior.2025.101090","DOIUrl":"10.1016/j.jbior.2025.101090","url":null,"abstract":"<div><h3>Purpose</h3><div>Immunity, stemness, and DNA damage repair (DDR) are crucial for cancer development and therapy resistance. With advancements in multiomics technology, the exploration of cancers related to immunity, stemness, and the DDR has triggered interest, but the combination of these levels for analyzing multiple cancers remains insufficient.</div></div><div><h3>Methods</h3><div>In this study, 9906 solid tumor samples from 31 TCGA cancer types were clustered on the basis of the enrichment levels of 13 gene sets associated with stemness, immunity, and DDR. Moreover, a soft ensemble model was constructed on the basis of the enrichment levels of these 13 gene sets to predict cancer subtypes via other omics data.</div></div><div><h3>Results</h3><div>We identified four pancancer subtypes, termed C1, C2, C3, and C4, which presented distinct molecular and clinical features, including the immune microenvironment, stemness, genome instability, intratumor heterogeneity, methylation levels, tumor progression, sensitivity to chemotherapy and immunotherapy, and survival prognosis. The soft ensemble model validated this subtyping method in two breast cancer datasets (gene expression level), a pancancer proteomic dataset (protein expression level), and a pancancer cell line dataset (cell line gene expression level).</div></div><div><h3>Conclusion</h3><div>Our findings indicate that immune, stemness, and DDR signature-based subtyping offers new perspectives on cancer biology and holds promise for improving the clinical management of cancers.</div></div>","PeriodicalId":7214,"journal":{"name":"Advances in biological regulation","volume":"96 ","pages":"Article 101090"},"PeriodicalIF":0.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143895904","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":"Lysophosphatidic acid (LPA) receptor signaling modulates cellular functions of colon cancer cells under cobalt chloride-induced hypoxic conditions","authors":"Mao Yamamoto, Miwa Takai, Narumi Yashiro, Moemi Tamura, Yuka Kusumoto, Shion Nagano, Anri Taniguchi, Nanami Shimomura, Toshifumi Tsujiuchi","doi":"10.1016/j.jbior.2025.101098","DOIUrl":"10.1016/j.jbior.2025.101098","url":null,"abstract":"<div><div>In the tumor microenvironment (TME), hypoxia is critical in promoting tumor invasiveness and progression. Cobalt chloride (CoCl<sub>2</sub>) mimics hypoxia by inducing comparable cellular responses. Lysophosphatidic acid (LPA) receptors (LPA<sub>1</sub> to LPA<sub>6</sub>) play key roles in regulating cancer cell functions. In this study, we investigated the impact of LPA receptor signaling on malignant properties of colon cancer DLD-1 cells under hypoxic condition induced by CoCl<sub>2</sub>. <em>LPAR1</em> and <em>LPAR2</em> expression levels were elevated in DLD-1 cells treated with CoCl<sub>2</sub>. CoCl<sub>2</sub> treatment also stimulated DLD-1 cell motility. This enhanced motility induced by CoCl<sub>2</sub> was reduced with LW6 (HIF-1 inhibitor). Additionally, the motility of CoCl<sub>2</sub>-treated DLD-1 cells was suppressed by AM966 (LPA<sub>1</sub> antagonist) and enhanced by GRI-977143 (LPA<sub>2</sub> agonist). Conversely, CoCl<sub>2</sub> treatment decreased DLD-1 cell invasion. While AM966 further inhibited cell invasion, GRI-977143 elevated it. The cell viability to fluorouracil (5-FU) was higher in CoCl<sub>2</sub>-treated DLD-1 cells. This increased viability to 5-FU was further enhanced by both AM966 and GRI-977143. When CoCl<sub>2</sub>-treated DLD-1 cells were cultured in low-glucose media, <em>LPAR1</em> expression was upregulated compared to high-glucose media, while <em>LPAR2</em> expression was downregulated. Additionally, motility and invasion in CoCl<sub>2</sub>-treated DLD-1 cells were further stimulated under low-glucose conditions. These results suggest that LPA receptor signaling contributes to the malignant potential of DLD-1 cells in a hypoxic environment induced by CoCl<sub>2</sub> treatment.</div></div>","PeriodicalId":7214,"journal":{"name":"Advances in biological regulation","volume":"96 ","pages":"Article 101098"},"PeriodicalIF":0.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143918005","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}
Franceine S Welcome, Taisha C M Elizaire, Michael V Airola
{"title":"Lipin phosphatidic acid phosphatases: Structure, function, regulation, and disease association.","authors":"Franceine S Welcome, Taisha C M Elizaire, Michael V Airola","doi":"10.1016/j.jbior.2025.101082","DOIUrl":"https://doi.org/10.1016/j.jbior.2025.101082","url":null,"abstract":"<p><p>Lipids play essential roles as structural barriers in cell membranes, long-term energy storage, and as signaling molecules. One class of enzymes involved in lipid synthesis are lipins. Lipins are magnesium-dependent phosphatidic acid phosphatases that produce diacylglycerol, playing key roles in TAG synthesis, de novo phospholipid synthesis and metabolism. Here, we review recent advances on the structure, function, and regulation of lipins with a particular focus on the structural impacts of missense mutations associated with rhabdomyolysis, Majeed syndrome and neuropathies. Structural insights reveal that while some disease-associated mutations directly disrupt catalysis, many missense mutations are not near the active site, but still play a key role in PAP activity. With the resolved crystal structure of a lipin homolog Tt Pah2, AlphaFold, and AlphaMissense it has become increasingly possible to predict the pathogenicity and structural contributions of individual residues and mutations. Going forward, this structural information can be used to predict and understand new mutations as they arise.</p>","PeriodicalId":7214,"journal":{"name":"Advances in biological regulation","volume":" ","pages":"101082"},"PeriodicalIF":0.0,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143412894","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}
Agnieszka Gizak, Bartosz Budziak, Aleksandra Domaradzka, Łukasz Pietras, Dariusz Rakus
{"title":"Fructose 1,6-bisphosphatase as a promising target of anticancer treatment","authors":"Agnieszka Gizak, Bartosz Budziak, Aleksandra Domaradzka, Łukasz Pietras, Dariusz Rakus","doi":"10.1016/j.jbior.2024.101057","DOIUrl":"10.1016/j.jbior.2024.101057","url":null,"abstract":"<div><div>Fructose 1,6-bisphosphatase (FBP) is a regulatory enzyme of gluconeogenesis that also influences in a non-catalytic manner – via protein-protein interactions – cell cycle-dependent events, mitochondria biogenesis and polarization, synaptic plasticity and even cancer progression. FBP reduces glycolytic capacity of cells via blocking HIF-1α transcriptional activity and modulating NF-κB action, and influences oxidative metabolism by binding to c-MYC. Because FBP limits the energy-producing potential of cells and because a reduction of FBP amounts is observed in cancer cells, FBP is considered to be an anti-oncogenic protein. This is supported by the observation that cancer cells overexpress aldolase A (ALDOA), a pro-oncogenic protein that can bind to FBP and potentially block its anti-oncogenic activity. Interestingly, only the muscle isozyme of FBP (FBP2) interacts strongly with ALDOA, whereas the binding of the liver isozyme (FBP1) to ALDOA is more than an order of magnitude weaker.</div><div>Here, we briefly review the most important evidence supporting the anti-oncogenic function of FBP and discuss what structural properties of the two FBP isozymes allow FBP2, rather than FBP1, to exert more flexible anticancer functions.</div></div>","PeriodicalId":7214,"journal":{"name":"Advances in biological regulation","volume":"95 ","pages":"Article 101057"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142567265","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}
Xiaohan Yu , Carl J. Mousley , Vytas A. Bankaitis , Prasanna Iyer
{"title":"A budding yeast-centric view of oxysterol binding protein family function","authors":"Xiaohan Yu , Carl J. Mousley , Vytas A. Bankaitis , Prasanna Iyer","doi":"10.1016/j.jbior.2024.101061","DOIUrl":"10.1016/j.jbior.2024.101061","url":null,"abstract":"<div><div>The Trans Golgi Network (TGN)/endosomal system is a sorting center for cargo brought via the anterograde secretory pathway and the endocytic pathway that internalizes material from the plasma membrane. As many of the cargo that transit this central trafficking hub are components of key homeostatic signaling pathways, TGN/endosomes define a critical signaling hub for cellular growth control. A particularly interesting yet incompletely understood aspect of regulation of TGN/endosome function is control of this system by two families of lipid exchange/lipid transfer proteins. The phosphatidylinositol transfer proteins promote pro-trafficking phosphoinositide (i.e. phosphatidylinositol-4-phosphate) signaling pathways whereas proteins of the oxysterol binding protein family play reciprocal roles in antagonizing those arms of phosphoinositide signaling. The precise mechanisms for how these lipid binding proteins execute their functions remain to be resolved. Moreover, information regarding the coupling of individual members of the oxysterol binding protein family to specific biological activities is particularly sparse. Herein, we review what is being learned regarding functions of the oxysterol binding protein family in the yeast model system. Focus is primarily directed at a discussion of the Kes1/Osh4 protein for which the most information is available.</div></div>","PeriodicalId":7214,"journal":{"name":"Advances in biological regulation","volume":"95 ","pages":"Article 101061"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142754531","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":"Sixty-fifth international symposium on biological regulation and enzyme activity in normal and neoplastic tissues","authors":"","doi":"10.1016/j.jbior.2025.101077","DOIUrl":"10.1016/j.jbior.2025.101077","url":null,"abstract":"","PeriodicalId":7214,"journal":{"name":"Advances in biological regulation","volume":"95 ","pages":"Article 101077"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143421464","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}
Ana Miladinović , Ludovica Antiga , Tomáš Venit , Andrea Bayona-Hernandez , Jakub Červenka , Rajendra Kumar Labala , Michal Kolář , Enrique Castaño , Martin Sztacho , Pavel Hozák
{"title":"The perinucleolar compartment and the oncogenic super-enhancers are part of the same phase-separated structure filled with phosphatidylinositol 4,5-bisphosphate and long non-coding RNA HANR","authors":"Ana Miladinović , Ludovica Antiga , Tomáš Venit , Andrea Bayona-Hernandez , Jakub Červenka , Rajendra Kumar Labala , Michal Kolář , Enrique Castaño , Martin Sztacho , Pavel Hozák","doi":"10.1016/j.jbior.2024.101069","DOIUrl":"10.1016/j.jbior.2024.101069","url":null,"abstract":"<div><div>The liquid-liquid phase separation in the cell nucleus regulates various processes such as gene regulation and transcription control, chromatin organization, and DNA repair. A plethora of proteins and RNAs contribute to the formation of biomolecular condensates and recently, several nuclear phosphoinositides were shown to be a part of these membrane-less complexes within the nucleus as well. Here we lipid-interacting RNA sequencing (LIPRNAseq) and confocal microscopy to uncover the RNA-binding capacity and localization of phosphatidylinositol 4,5 bisphosphate (PIP2). We discovered the consensus PIP2-binding AU-rich RNA motif and identified long non-coding RNA HANR (lncHANR) to colocalize with PIP2 in the proximity to the nucleolus in the perinucleolar compartment (PNC). Colocalization studies with different nuclear markers reveal that PIP2-HANR presence in the PNC correlates with oncogenic super-enhancers, and both PNC and oncogenic enhancers are part of the same structure. As lncHANR, PNC, and oncogenic super-enhancers are associated with cancer cell lines and tumors, we suggest that they can serve as interchangeable prognostic markers. Understanding of the interplay between lipid metabolism, and lncRNAs in subnuclear compartment phase separation can lead to future improvement in treatment strategies and personalized cancer management approaches.</div></div>","PeriodicalId":7214,"journal":{"name":"Advances in biological regulation","volume":"95 ","pages":"Article 101069"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142794309","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}
Eleonora Ceneri , Alessia De Stefano , Irene Casalin , Carlo Finelli , Antonio Curti , Stefania Paolini , Sarah Parisi , Federica Ardizzoia , Gianluca Cristiano , Jaqueline Boultwood , James A. McCubrey , Pann-Ghill Suh , Giulia Ramazzotti , Roberta Fiume , Stefano Ratti , Lucia Manzoli , Lucio Cocco , Matilde Y. Follo
{"title":"Signaling pathways and bone marrow microenvironment in myelodysplastic neoplasms","authors":"Eleonora Ceneri , Alessia De Stefano , Irene Casalin , Carlo Finelli , Antonio Curti , Stefania Paolini , Sarah Parisi , Federica Ardizzoia , Gianluca Cristiano , Jaqueline Boultwood , James A. McCubrey , Pann-Ghill Suh , Giulia Ramazzotti , Roberta Fiume , Stefano Ratti , Lucia Manzoli , Lucio Cocco , Matilde Y. Follo","doi":"10.1016/j.jbior.2024.101071","DOIUrl":"10.1016/j.jbior.2024.101071","url":null,"abstract":"<div><div>Key signaling pathways within the Bone Marrow Microenvironment (BMM), such as Notch, Phosphoinositide-Specific Phospholipase C (PI-PLCs), Transforming Growth Factor β (TGF-β), and Nuclear Factor Kappa B (NF-κB), play a vital role in the progression of Myelodysplastic Neoplasms (MDS). Among the various BMM cell types, Mesenchymal Stromal Cells (MSCs) are particularly central to these pathways. While these signaling routes can independently affect both MSCs and Hematopoietic Stem Cells (HSCs), they most importantly alter the dynamics of their interactions, leading to abnormal changes in survival, differentiation, and quiescence. Notch and PI-PLC signaling facilitate intercellular communication, TGF-β promotes quiescence and suppresses hematopoiesis, and NF-κB-driven inflammatory responses foster an environment detrimental to normal hematopoiesis. This review highlights the role of these pathways within the MDS microenvironment, driving the development and progression of the disease and paving the way for new possible therapeutic strategies.</div></div>","PeriodicalId":7214,"journal":{"name":"Advances in biological regulation","volume":"95 ","pages":"Article 101071"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142794342","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}
Grace Q. Gong , Madhangopal Anandapadamanaban , Md Saiful Islam , Iain M. Hay , Maxime Bourguet , Saulė Špokaitė , Antoine N. Dessus , Yohei Ohashi , Olga Perisic , Roger L. Williams
{"title":"Making PI3K superfamily enzymes run faster","authors":"Grace Q. Gong , Madhangopal Anandapadamanaban , Md Saiful Islam , Iain M. Hay , Maxime Bourguet , Saulė Špokaitė , Antoine N. Dessus , Yohei Ohashi , Olga Perisic , Roger L. Williams","doi":"10.1016/j.jbior.2024.101060","DOIUrl":"10.1016/j.jbior.2024.101060","url":null,"abstract":"<div><div>The phosphoinositide 3-kinase (PI3K) superfamily includes lipid kinases (PI3Ks and type III PI4Ks) and a group of PI3K-like Ser/Thr protein kinases (PIKKs: mTOR, ATM, ATR, DNA-PKcs, SMG1 and TRRAP) that have a conserved C-terminal kinase domain. A common feature of the superfamily is that they have very low basal activity that can be greatly increased by a range of regulatory factors. Activators reconfigure the active site, causing a subtle realignment of the N-lobe of the kinase domain relative to the C-lobe. This realignment brings the ATP-binding loop in the N-lobe closer to the catalytic residues in the C-lobe. In addition, a conserved C-lobe feature known as the PIKK regulatory domain (PRD) also can change conformation, and PI3K activators can alter an analogous PRD-like region. Recent structures have shown that diverse activating influences can trigger these conformational changes, and a helical region clamping onto the kinase domain transmits regulatory interactions to bring about the active site realignment for more efficient catalysis. A recent report of a small-molecule activator of PI3Kα for application in nerve regeneration suggests that flexibility of these regulatory elements might be exploited to develop specific activators of all PI3K superfamily members. These activators could have roles in wound healing, anti-stroke therapy and treating neurodegeneration. We review common structural features of the PI3K superfamily that may make them amenable to activation.</div></div>","PeriodicalId":7214,"journal":{"name":"Advances in biological regulation","volume":"95 ","pages":"Article 101060"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142724465","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}