Journal of Pharmacology and Experimental Therapeutics最新文献

{"title":"PHLDA2 in cancer: From molecular mechanisms to therapeutic opportunities.","authors":"Qingqing Wan, Mi Zhang, Wantao Chen, Xu Wang","doi":"10.1016/j.jpet.2025.103677","DOIUrl":"10.1016/j.jpet.2025.103677","url":null,"abstract":"<p><p>Pleckstrin homology-like domain, family A, member 2 (PHLDA2), an imprinted gene located on human chromosome 11p15.5, has emerged as a critical player in cancer biology with complex dual roles as both tumor suppressor and oncogene. This review synthesizes recent advances in understanding the mechanistic contributions of PHLDA2 to tumorigenesis, highlighting novel insights into its regulation of cellular processes, including apoptosis, autophagy, and ferroptosis, across diverse cancer types. We provide the first comprehensive comparative analysis of the context-dependent functions of PHLDA2, revealing how tumor microenvironment and cancer type determine its oncogenic versus tumor-suppressive roles. Key innovations addressed include the discovery of the role of PHLDA2 in ferroptosis through its interaction with ALOX12, its regulation of the PI3K/protein kinase B (AKT) pathway via competitive membrane binding, and its emerging potential as both a diagnostic biomarker and therapeutic target. The review critically examines current challenges in translating PHLDA2 research into clinical applications and identifies priority research directions for exploiting this protein's therapeutic potential in precision cancer medicine. SIGNIFICANCE STATEMENT: Pleckstrin homology-like domain, family A, member 2 functions as both oncogene and tumor suppressor across cancer types, regulating apoptosis, autophagy, and ferroptosis. Its dual roles and posttranslational modifications present novel opportunities for precision cancer diagnosis, prognosis, and targeted therapy development.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 9","pages":"103677"},"PeriodicalIF":3.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145040041","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Antiproliferative effects of dihydrotanshinone I on autosomal dominant polycystic kidney disease via immunomodulation.","authors":"Rhubaniya Mahendran, Soo Kun Lim, Kien Chai Ong, Kek Heng Chua, Hwa Chia Chai","doi":"10.1016/j.jpet.2025.103655","DOIUrl":"10.1016/j.jpet.2025.103655","url":null,"abstract":"<p><p>Autosomal dominant polycystic kidney disease (ADPKD) is a hereditary kidney disorder affecting individuals worldwide and is one of the leading causes of end-stage renal disease. Based on the shared pathogenic mechanisms between cancer and ADPKD, we explored the potential of repurposing dihydrotanshinone I (DHTS), a compound previously shown to possess anticancer properties, for ADPKD treatment. Using sulforhodamine B cytotoxic and real-time cell analysis, we evaluated the effects of various DHTS concentrations on WT 9-12 (ADPKD) cells for up to 72 hours. Our results revealed a concentration-dependent decrease in WT 9-12 cell viability, with minimal impact on HK-2 (normal kidney) cells. Notably, 32 μM DHTS was identified with an IC₅₀ after 24 hours of treatment on WT 9-12 cells. Cell cycle analysis further indicated that 32 μM DHTS-induced G1 phase arrest in WT 9-12 cells. We determined that DHTS has a preference for necrosis over apoptosis in WT 9-12 cells in the apoptosis analysis. To elucidate the underlying molecular mechanisms, we employed isobaric tags for relative and absolute quantitation-based proteomic analysis to identify differentially expressed proteins and reveal their intricate interplay and the signaling pathways modulated by DHTS treatment. Some of our key findings include enhanced immune surveillance and its role in suppressing metabolic pathways that promote ADPKD progression in WT 9-12 cells prior to DHTS treatment. After DHTS exposure, these pathways appeared to be modulated, with a potential restoration of extracellular matrix regulation. However, DHTS treatment may have failed to reinstate metabolic suppression in untreated WT 9-12 cells. Overall, our results highlight the therapeutic potential of DHTS in slowing ADPKD progression, offering promise for a safer and more effective treatment approach that targets the underlying disease mechanisms rather than merely managing symptoms. SIGNIFICANCE STATEMENT: This study found that dihydrotanshinone I (DHTS) suppressed autosomal dominant polycystic kidney disease (ADPKD) cell proliferation through G1 phase cell cycle arrest and enhanced necrosis. DHTS treatment may also modulate the increased immune surveillance shown in untreated ADPKD cells. Upon understanding its implicated signaling pathways and assuring its safety on normal cells, the DHTS-induced antiproliferative effects on ADPKD cells prove the potential of DHTS as alternative treatment for ADPKD.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 9","pages":"103655"},"PeriodicalIF":3.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144794775","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Coated nanoparticles enhance immune efficacy of Helicobacter pylori outer membrane vesicles by activating Th1/Th2/Th17 responses.","authors":"Songling Ye, Jin Liu, Shiyuan Huang, Luo Chen, Xinyi Zeng, Jingjing Zhao, Suqing Zhao","doi":"10.1016/j.jpet.2025.103669","DOIUrl":"10.1016/j.jpet.2025.103669","url":null,"abstract":"<p><p>Antibiotic resistance has emerged as a pressing global public health crisis. The development of a safe and efficient Helicobacter pylori vaccine has become an important measure to eradicate Hpylori infection. Outer membrane vesicles (OMVs) secreted by Gram-negative bacteria are immunogenic and have received increasing attention in the development of vaccines against bacterial infections. In this study, Hpylori was used as a model pathogen, Hpylori outer membrane vesicle (HM) as an antigen, and dendritic mesoporous organosilica nanoparticles (DMON) as a carrier to load lipopolysaccharide (LPS) as an adjuvant to obtain a stable LPS@DMON@HM vaccine. The nanovaccine markedly enhanced the phagocytosis of macrophages and the secretion of IL-4, IFN-gamma, and IL-17A in vitro. In vivo, LPS@DMON@HM can significantly increase the specific antibody titer, and the serum-specific IgG antibody titer after vaccine immunization can reach 1:12,800, which is 16 times that of free HM immunization. Further studies indicated that the levels of Th1, Th2, and Th17 cytokines in spleen cells were induced to show a marked elevation. The results showed that LPS@DMON@HM had stronger immunogenicity and induced higher levels of humoral immunity, mucosal immunity, and Th1/Th2/Th17 cellular immune responses compared with free HM. The vaccine exhibited no toxicity at the tested doses. This study establishes a mechanistic foundation for developing next-generation Hpylori vaccines with optimized safety-efficacy profiles and simultaneously offers a reference for the development of vaccines against other Gram-negative pathogens. SIGNIFICANCE STATEMENT: Infection with Helicobacter pylori is closely associated with a wide range of gastrointestinal diseases; however, antibiotic resistance has been significantly undermining its therapeutic efficacy. The LPS@DMON@HM nanovaccine developed in this study can induce high levels of anti-Hpylori IgG after immunization of mice and can also induce mucosal immunity and Th1/Th2/Th17 mixed immune responses. It is anticipated to be further investigated as a nonantibiotic therapeutic option for Hpylori infection.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 9","pages":"103669"},"PeriodicalIF":3.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144883075","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Human myocardial-derived highly proliferative cells improve cardiac remodeling after myocardial infarction in mice.","authors":"Michayla Moore, Elena Chepurko, Vadim Chepurko, Calvin Vary, Sergey Ryzhov, Douglas B Sawyer","doi":"10.1016/j.jpet.2025.103673","DOIUrl":"10.1016/j.jpet.2025.103673","url":null,"abstract":"<p><p>Human highly proliferative cells (hHiPCs) isolated from the adult heart have progenitor and angiogenic properties. However, the mechanisms underlying hHiPCs in myocardial repair in vivo have yet to be investigated. We characterized the hHiPC proteome and secretome and found that hHiPCs express and secrete proangiogenic and proreparative proteins, including CXCL6, CTHRC1, and CD73, and are ontologically enriched in pathways related to cytokine signaling and glucose metabolism. Using publicly available single-cell data (GSE149699), we found that CXCL6, CTHRC1, and CD73 are also expressed in adult and neonatal cardiospheres, resembling a therapeutic cell population currently being tested in clinical trials. With the prominent role of these enriched secreted factors in cardiac repair and highly proliferative phenotype, we hypothesized that hHiPC injection would improve heart function following ischemic injury. Following experimental myocardial infarction (MI) in immunocompromised male and female mice, we found that intramyocardial injection of hHiPCs (2.5 × 10⁵ cells) resulted in ∼3.5% (∼8.7 × 10³ cells) survival in the host myocardium; however, hHiPC survival persisted throughout the acute phase of MI. To assess cardiac function after treatment, we found that hHiPCs improved fractional shortening by 21 and 28 days post-MI and prevented progressive ventricular remodeling compared with vehicle control treatment. Together, these data establish a role for hHiPCs in cardiac repair and lay the foundation for their investigation as a potential treatment for myocardial ischemic injury. SIGNIFICANCE STATEMENT: This study determined the unique novel properties of cardiac-derived human highly proliferative cells (hHiPCs) to survive over the acute inflammatory phase in the ischemic myocardium. hHIPCs were identified as potential candidates for cell-based therapy to create a long-term prohealing microenvironment by secreting proreparative proteins CXCL6, CTHRC1, and CD73.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 9","pages":"103673"},"PeriodicalIF":3.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144958317","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impacts of anti-drug antibodies on pharmacokinetic and pharmacodynamic actions of cell-permeable middle molecule peptide drug.","authors":"Mengxuan Gao, Ryota Saito, Hiroo Watanabe, Tomofumi Shimojo, Taichi Akahoshi, Shino Kuramoto, Tatsuhiko Tachibana","doi":"10.1016/j.jpet.2025.103663","DOIUrl":"10.1016/j.jpet.2025.103663","url":null,"abstract":"<p><p>The administration of peptide drugs can induce the generation of anti-drug antibodies (ADAs), potentially leading to unwanted effects such as reduced drug efficacy, which is often seen with therapeutic monoclonal antibodies. However, the influence of ADAs on the pharmacokinetic and pharmacodynamic properties of cell-permeable middle molecules remains unclear. This study investigated ADA impacts using AP2151, a middle molecule cyclic peptide with high cell membrane permeability. ADAs were generated by immunizing rabbits with an AP2151 analog conjugated to keyhole limpet hemocyanin. A dialysis experiment was then performed to determine the binding affinity between AP2151 and the purified ADAs. Using in-house experimental data, we established a SimBiology model to simulate the pharmacokinetic profiles of AP2151 in varying ADA concentrations. The simulation results suggested that higher ADA levels (up to several micromolar) would more strongly increase the total plasma concentrations of AP2151 without apparently changing the free concentrations. Thus, according to the free drug theory, the pharmacological effect was predicted to remain constant despite the presence of ADAs. These predictions were subsequently confirmed by an in vivo study, in which mice were administered with AP2151 following a preliminary infusion with or without ADAs. Our findings suggest that in the case of cell-permeable middle molecules, ADAs raise total drug concentrations but have little impact on the drug efficacy. SIGNIFICANCE STATEMENT: We conducted both model-based simulation and in vivo experiments to examine anti-drug antibody impacts on a cell-permeable middle molecule drug. As predicted by the model and confirmed by mouse studies, the presence of anti-drug antibodies increases the total plasma concentration of the drug without compromising its pharmacological effects, highlighting the significance of model analysis and may contribute to the understanding of middle molecule compounds.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 9","pages":"103663"},"PeriodicalIF":3.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144847129","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effects of Δ⁹-tetrahydrocannabinol (THC), cannabidiol (CBD), and THC:CBD mixtures on behavioral and physiological signs of morphine withdrawal in rhesus monkeys.","authors":"Lawrence M Carey, Lindsey K Galbo-Thomma, David R Maguire, Charles P France","doi":"10.1016/j.jpet.2025.103671","DOIUrl":"10.1016/j.jpet.2025.103671","url":null,"abstract":"<p><p>The mu-opioid receptor agonists methadone and buprenorphine are effective for treating opioid use disorder (OUD); however, both drugs are diverted and misused and withdrawal signs can emerge when treatment is tapered or discontinued. Mu-opioid and cannabinoid type 1 receptors are colocalized in several brain regions, and cannabinoids have been proposed as potential treatments for opioid withdrawal. This study tested Δ⁹-tetrahydrocannabinol (THC) and cannabidiol (CBD), alone and in mixtures, for treating the behavioral and physiological signs of morphine withdrawal in 3 male rhesus monkeys. The α₂-adrenergic receptor agonist lofexidine was also tested. Monkeys received escalating doses of morphine up to 3.2 mg/kg twice daily. After at least 2 weeks of morphine treatment, saline was substituted for morphine for 2 days. Behavioral and physiological signs of opioid withdrawal, including blood pressure, heart rate, body temperature, and activity were measured before and after administration of THC (0.32-1.0 mg/kg), CBD (10-17.8 mg/kg), mixtures of THC (0.32 mg/kg) and CBD (10-17.8 mg/kg), lofexidine (0.032-0.32 mg/kg), or vehicle. Discontinuing morphine treatment markedly increased unusual tongue movements, a characteristic behavioral sign of opioid withdrawal in monkeys, and all physiological signs. The largest THC dose (1.0 mg/kg) decreased unusual tongue movements and heart rate, and the largest lofexidine dose (0.32 mg/kg) decreased unusual tongue movements, blood pressure, heart rate, and activity. CBD alone or with THC had no significant effect. These data demonstrate that THC attenuates some signs of opioid withdrawal; however, THC was not more effective than the currently available medication lofexidine. SIGNIFICANCE STATEMENT: Δ⁹-Tetrahydrocannabinol (THC) alone, but not cannabidiol either alone or in combination with THC, decreased some behavioral and physiological signs of opioid withdrawal in monkeys. However, those effects of THC were not greater than the effects of the currently available nonopioid medication lofexidine.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 9","pages":"103671"},"PeriodicalIF":3.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144958319","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Phenotypic pharmacology of novel Complex I inhibitors eliciting tissue repair concurrent to control of inflammation.","authors":"Lisa Patel, Fatima Garcia-Raposo, Benjamin Moore, James Wood, Lily Morley, David Loczenski, Stephen A Smith, Puneeta Nath, Nicholas Holliday, Sam Williams, Iain R Greig, Paul Vink, Martyn L Foster","doi":"10.1016/j.jpet.2025.103661","DOIUrl":"10.1016/j.jpet.2025.103661","url":null,"abstract":"<p><p>A key challenge of regenerative medicine is to provide a signal that can promote and regulate the repair and maintenance of tissues and organ systems to overcome progressive decline. Profiling of novel inhibitors of mitochondrial Complex I (NIC1s) showed differential effects on myeloid and fibroblast cells in vitro and revealed augmented and anatomically appropriate tissue repair in vivo. In a mouse model of collagen-induced arthritis, therapeutic treatment with NIC1s reduced inflammation and bone pathology and concurrently improved the production of anatomically appropriate osteoid, indicative of an osteoblastogenic repair response. In a bleomycin-induced lung fibrosis model, treatment with NIC1s reduced fibrosis and inflammation and mobilized a controlled and appropriate alveolar epithelial repair response that preceded overt antifibrotic and anti-inflammatory effects. We hypothesize that these findings are consistent with a hormetic model of mitochondrial stress transduction, which leads to constrained cell fate selection in myeloid and fibroblast cells. Our work characterizes a new class of Complex I inhibitors and suggests that Complex I may act as a signaling checkpoint to promote and regulate context-dependent repair responses in vivo. SIGNIFICANCE STATEMENT: A key challenge of regenerative medicine is to promote and regulate the repair and maintenance of tissues and organ systems to overcome progressive decline. Augmented and anatomically appropriate tissue repair was demonstrated in disease models of arthritis and lung injury concurrent to ongoing inflammation and/or fibrosis and elicited by a novel mechanistic transduction of mitochondrial stress. These findings provide proof-of-concept for the pharmacological induction of tissue repair using novel inhibitors of mitochondrial Complex I, with important therapeutic implications.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 9","pages":"103661"},"PeriodicalIF":3.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144812177","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nicotine enhances the ability of cues to control behavior and evoke dopamine release in the dorsolateral striatum.","authors":"Michael Z Leonard, Hannah B Elam, Hye Jean Yoon, Sofia H Lago, Megan E Altemus, Shemuel Roberts, Maxime Chevée, Erin S Calipari","doi":"10.1016/j.jpet.2025.103662","DOIUrl":"10.1016/j.jpet.2025.103662","url":null,"abstract":"<p><p>Nicotine is one of the most widely used addictive substances, yet its primary reinforcing effects are relatively weak. Nicotine's ability to potentiate responding for conditioned reinforcers is thought to drive persistent drug use. Here, we show that nicotine failed to alter responding maintained by a primary sucrose reinforcer (under a variable-ratio [VR] 11 schedule) across a broad dose range (0.01-1.0 mg/kg). Yet, nicotine enhanced operant behavior under a second-order reinforcement schedule in which responses produced sucrose-associated cues and were only intermittently reinforced by sucrose itself. Together, we demonstrate that nicotine selectively augments behavior maintained by conditioned reinforcers (sucrose-associated cues) in a rate-dependent manner, increasing responding only in mice with low rates of reinforcement behavior at baseline. Using fiber photometry, we demonstrate that nicotine selectively amplified cue-evoked dopamine release in the dorsolateral striatum-but only in low baseline responders-while having no effect on dopamine signaling in the nucleus accumbens. These effects were blocked by the nicotinic receptor antagonist mecamylamine. Further, nicotine's influence on behavior was abolished when the contingency between action and conditioned stimuli was disrupted, indicating that nicotine strengthens cue control of behavior rather than increasing motivation generally. Collectively, these findings reveal that nicotine's behavioral actions emerge through an interaction between pharmacological mechanisms, behavioral contingencies, and individual differences in baseline behavioral control. SIGNIFICANCE STATEMENT: Nicotine strengthens the impact of environmental cues on behavior by amplifying dopamine signals in specific projection targets, but only in individuals with specific behavioral traits. This reveals how nicotine hijacks learning processes to promote persistent, cue-driven actions.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 9","pages":"103662"},"PeriodicalIF":3.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144855614","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Remodeling the sarcoma microenvironment by simultaneous targeting of urokinase-type plasminogen activator receptors and epidermal growth factor receptors to promote antitumor activity.","authors":"Ashley J Schulte, Mitzi Lewellen, Willa Durose, Erin Nolan, Leyla Taghizadeh, Deborah Todhunter, Courtney Bush, Haeree P Lang, Mary E Brown, Taylor A DePauw, Kelly M Makielski, Jong Hyuk Kim, Lauren E Burt, Paula Overn, Colleen L Forster, Davis M Seelig, M Gerard O'Sullivan, Brenda J Weigel, Paari Murugan, Gary R Cutter, Troy C Lund, Daniel A Vallera, Jaime F Modiano","doi":"10.1016/j.jpet.2025.103674","DOIUrl":"10.1016/j.jpet.2025.103674","url":null,"abstract":"<p><p>We evaluated the antitumor effects of remodeling the MC17 mouse sarcoma microenvironment (SME) by targeting urokinase-type plasminogen activator receptor (uPAR)- and epidermal growth factor receptor (EGFR)-expressing cells. Specifically, we used eBAT (a bispecific ligand-targeted toxin directed to EGFR and uPAR), and its mouse counterpart, meBAT, to ablate uPAR- and/or EGFR-expressing cells. We chose the MC17 model because the cells are resistant to eBAT, allowing us to exclusively evaluate the role of uPAR- and EGFR-expressing cells in the SME. Our results show that uPAR expression, both by the tumor cells and by the SME, was dispensable for tumor formation. However, uPAR-deficient tumors grew considerably slower than uPAR-expressing tumors. To specifically address mechanisms responsible for antitumor effects of remodeling the SME, we used uPAR-knockout bone marrow chimeras. In uPAR-replete chimeras, systemic administration of eBAT or meBAT depleted tumor-associated macrophages, increased the proportion of phagocytic myeloid cells, and promoted T cell infiltration into the SME, which was associated with delayed tumor growth. All of these effects were reduced or abrogated in uPAR-deficient bone marrow chimeras. We conclude that targeting uPAR- and EGFR-expressing stromal cells led to remodeling of the inflammatory SME, diminished tumor-associated immunosuppression, and improved survival of mice with transplantable sarcomas. SIGNIFICANCE STATEMENT: This study demonstrated that targeting urokinase-type plasminogen activator receptor- and/or epidermal growth factor receptor-expressing cells in the sarcoma microenvironment reprograms tumor-associated inflammation, leading to delayed progression in an aggressive, therapy-resistant mouse model of fibrosarcoma. The results indicate that the therapeutic benefit of remodeling the inflammatory microenvironment is achieved by making the tumors more visible to the immune system, highlighting the potential to incorporate this novel strategy into the management of advanced, treatment-refractory sarcomas.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 9","pages":"103674"},"PeriodicalIF":3.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145015673","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transient receptor potential vanilloid type 4 channels mediate bladder cancer cell proliferation, migration, and chemoresistance.","authors":"Venkatesh Katari, Kesha Dalal, Narendra Kondapalli, Sailaja Paruchuri, Nagalakshmi Nadiminty, Charles K Thodeti","doi":"10.1016/j.jpet.2025.103665","DOIUrl":"10.1016/j.jpet.2025.103665","url":null,"abstract":"<p><p>Bladder cancer (BLCA) is the second most common urologic cancer in the United States and worldwide and mostly affects the aging population. Despite several ongoing clinical trials, treatment paradigms for BLCA have not changed significantly. Here, we investigated the expression of transient receptor potential vanilloid type 4 (TRPV4) in patients with BLCA and its role in calcium influx, cell proliferation, and migration using normal human urothelial cells and BLCA cells. Bioinformatic analysis of the University of Alabama at Birmingham Cancer Data Analysis Portal and cBioPortal databases revealed that TRPV4 expression is significantly higher in human BLCA tissues than in normal adjacent tissues. Furthermore, TRPV4 expression was markedly elevated in early-stage BLCA and upregulated in muscle-invasive bladder cancer tissues. TRPV4 is expressed in both normal urothelial (SV-HUC-1) and BLCA (T-24) cells, and functional assays demonstrated enhanced TRPV4-mediated calcium influx in T-24 compared with SV-HUC-1 cells. T-24 cells exhibited higher spreading on extracellular matrix gels with increasing stiffness (0.2, 8, and 50 kPa) and exhibited a migratory phenotype compared to SV-HUC-1 cells. Pharmacological inhibition of TRPV4 significantly reduced proliferation and migration in T-24 cells but had minimal effects on normal cells. Finally, treatment with cisplatin significantly reduced TRPV4 protein levels and TRPV4-mediated calcium influx in chemosensitive UM-UC-3 cells but remained unchanged in chemoresistant T-24 cells, suggesting a potential role of TRPV4 in chemoresistance. In conclusion, TRPV4 may contribute to BLCA progression by regulating cell proliferation and migration and may impart resistance to chemotherapy. Targeting TRPV4 could present a novel therapeutic approach for managing BLCA progression and overcoming chemoresistance. SIGNIFICANCE STATEMENT: This study identified transient receptor potential vanilloid type 4 (TRPV4) as a critical driver of bladder cancer (BLCA) progression. TRPV4 gene expression is elevated in both early-stage and muscle-invasive BLCA tissues. Importantly, TRPV4 inhibition selectively reduces BLCA growth and motility. Furthermore, TRPV4 is downregulated by cisplatin in chemosensitive but not chemoresistant BLCA cells, underscoring its key role in bladder cancer chemoresistance. These findings position TRPV4 as a therapeutic target for enhancing BLCA treatment and overcoming drug resistance.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 9","pages":"103665"},"PeriodicalIF":3.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144847130","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}