Biochemical pharmacology最新文献

{"title":"Corrigendum to “The novel small molecule BH3 mimetic nobiletin synergizes with vorinostat to induce apoptosis and autophagy in small cell lung cancer” [Biochem. Pharmacol. 216 (2023) 115807]","authors":"Yu-qian Li , Fang Fan , Yuan-ru Wang , Lu-yao Li , Ya-jun Cao , Si-meng Gu , Shuai-shuai Liu , Yue Zhang , Jie Wang , Lu Tie , Yan Pan , Hui-fang Li , Xue-jun Li","doi":"10.1016/j.bcp.2025.116873","DOIUrl":"10.1016/j.bcp.2025.116873","url":null,"abstract":"","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"236 ","pages":"Article 116873"},"PeriodicalIF":5.3,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143644384","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Histone lactylation facilitates MCM7 expression to maintain stemness and radio-resistance in hepatocellular carcinoma","authors":"Zijian Liu ,&nbsp;Jiaqi Han ,&nbsp;Shitong Su ,&nbsp;Qiwen Zeng ,&nbsp;Zhenru Wu ,&nbsp;Jingsheng Yuan ,&nbsp;Jian Yang","doi":"10.1016/j.bcp.2025.116887","DOIUrl":"10.1016/j.bcp.2025.116887","url":null,"abstract":"<div><div>Cancer stem cells (CSCs) play an essential role in tumor initiation and therapy resistance. Histone lactylation as a novel epigenetic modification could regulate the gene transcription process during tumor progression. Nevertheless, researches have not well examined its role in maintaining CSC properties. Our study identified Minichromosome maintenance complex component 7 (MCM7) as a candidate gene in Hepatocellular carcinoma (HCC) with diagnostic and prognostic values, and Real-time quantitative PCR (qRT-PCR), Western blot (WB), and Immunohistochemistry <strong>(</strong>IHC) assays ascertained its obviously higher expressions in HCC cells and tissues. Ectopic of MCM7 could increase the expression of CSC-related genes and enhance spheroid both in size and in number. Suppression of MCM7 could strengthen the efficacy of radiotherapy verified by Cell counting kit-8 <strong>(</strong>CCK-8) and colony formation assays. The subcutaneous xenograft model indicated that suppression of MCM7 could inhibit CSC properties and the efficacy of radiotherapy in vivo. Mechanistically, histone lactylation could facilitate MCM7 expression, and both messenger RNA (mRNA) and protein level of MCM7 expression presented an obvious decrease due to 2-DG (glycolysis inhibitor) treatment and an obvious increase due to Rotenone (glycolysis activator) treatment. Rescue experiments verified that histone lactylation was necessary for MCM7 to promote CSC properties and radio-resistance in HCC. Arsenic trioxide (ATO) targeting MCM7 could inhibit the CSC phenotypes and enhance the efficacy of radiotherapy in vivo and in vitro. Collectively, histone lactylation could transcriptionally activate MCM7 to accelerate proliferation and radio-resistance through enhancing CSC properties. ATO targeting MCM7 could inhibit CSCs phenotypes and synergistically increase the efficacy of radiation therapy.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"236 ","pages":"Article 116887"},"PeriodicalIF":5.3,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143672892","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SLX4 and XPF are involved in cell migration and EMT in a cell-specific manner","authors":"Emeline Cros-Perrial ,&nbsp;Sabine Beaumel ,&nbsp;Manon Gimbert ,&nbsp;Ninon Camus ,&nbsp;Clara Vicente ,&nbsp;Imane Sekiou ,&nbsp;Léa Figuet ,&nbsp;Michaël Duruisseaux ,&nbsp;Charles Dumontet ,&nbsp;Lars Petter Jordheim","doi":"10.1016/j.bcp.2025.116885","DOIUrl":"10.1016/j.bcp.2025.116885","url":null,"abstract":"<div><div>SLX4 and XPF are two proteins involved in DNA repair, but very little is known about their potential roles in other processes of cancer cell biology. We developed original cell models with CRISPR-Cas9-mediated knock-out of SLX4 and/or XPF using five different cell lines (A549, NCI-H1703, COLO-357, HT-29 and HEK-293 T), and performed characterization with cell biology experiments including migration assays, drug sensitivity testing, cell proliferation assessment and Western blots for relevant proteins. Results showed decreased migration of all models in HT-29 cells, of XPF-deficient COLO-357 cells and of SLX4-deficient HEK-293 T cells. Modified cell models had overall increased sensitivity to cisplatin and mitomycine C, and some models showed an increased frequency of double-stranded DNA damages. One NCI-H1703 cell model showed major karyotypic modifications, and epithelial to mesenchymal transition (EMT)-related proteins were modified in several models. Finally, knocking out one or both proteins in A549 cells had not the same impact on <em>in vivo</em> growth in mice. These original cell models allowed us to identify new and DNA repair-unrelated cellular roles of SLX4 and XPF in cancer cell biology. Our results should be considered within work on Nucleotide Excision Repair (NER) inhibition targeting SLX, XPF or other related proteins.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"236 ","pages":"Article 116885"},"PeriodicalIF":5.3,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143673207","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ultraviolet-treated riboflavin alleviates atopic dermatitis by inhibiting NLRP3 inflammasome activation and M1 macrophage polarization via histone lactylation","authors":"Shuang Ge ,&nbsp;Bingquan Qiu ,&nbsp;Ruining Liu ,&nbsp;Liping Sun ,&nbsp;Lu Yang ,&nbsp;Xinghui Chen ,&nbsp;Hongjin Tao ,&nbsp;Wei Yang ,&nbsp;Yang Yu ,&nbsp;Deqing Wang","doi":"10.1016/j.bcp.2025.116879","DOIUrl":"10.1016/j.bcp.2025.116879","url":null,"abstract":"<div><div>Atopic dermatitis (AD) is a chronic inflammatory skin disorder requiring improved therapeutic strategies. This study investigates the potential of ultraviolet (UV)-treated riboflavin in AD treatment. Using a MC903-induced mouse model, we demonstrate that topical UV-treated riboflavin significantly attenuates AD progression. Mechanistically, UV-treated riboflavin suppresses macrophage nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome activation by reducing histone H3 lysine 9 lactylation (H3K9la) on NLRP3 and apoptosis-associated speck-like protein containing a CARD (ASC) promoter, decreasing interleukin-1β (IL-1β) secretion and subsequent keratinocyte-derived thymic stromal lymphopoietin (TSLP) production. It also directly inhibits inflammatory cytokine expression in keratinocytes. NLRP3 activation in vivo partially reverses these effects, confirming the central role of NLRP3 inflammasome inhibition. Our findings reveal a novel epigenetic mechanism of UV-treated riboflavin in modulating immune responses in AD, highlighting its potential as a therapeutic strategy for inflammatory skin disorders.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"236 ","pages":"Article 116879"},"PeriodicalIF":5.3,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143673211","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Retrospective analysis and decentralized distribution to improve the lifecycle of Ah receptor research assets","authors":"Alex C. Veith ,&nbsp;Patrick R. Carney ,&nbsp;Aijing Wu ,&nbsp;Brenda L. Rojas ,&nbsp;Emmanuel Vazquez-Rivera ,&nbsp;Mark E. Berres ,&nbsp;Christopher Harrison ,&nbsp;C. Dustin Rubinstein ,&nbsp;Christopher A. Bradfield","doi":"10.1016/j.bcp.2025.116874","DOIUrl":"10.1016/j.bcp.2025.116874","url":null,"abstract":"<div><div>Scientific progress benefits from the sharing of “research assets” such as data, reagents, models, and experimental samples. To improve asset shareability, we evaluated the availability, quality, and characterization of recombinant DNA molecules, recombinant mouse models, and tissue samples described by our laboratory in ten publications spanning over thirty years. Employing state-of-the-art molecular technologies, we identified existing samples, updated their localization, generated modern sequences and maps of recombinant models, and ported the associated metadata to an internal blockchain-dependent resource using a standardized description for each asset class. We also created non-fungible tokens representing research assets on the public blockchain network Solana. In addition to providing an audit of previously reported shareable assets and improving the value of recombinant models, this re-analysis also provides evidence for the utility of extant tissue samples that may be difficult and expensive to regenerate. The results demonstrate how retrospective analysis can improve and expand upon the spectrum of shareable research assets through updates on molecular characterization and physical location, as well as improving the availability of biological samples of potential high experimental value. Moreover, the development of a decentralized ledger harboring this revised metadata provides a path to the description and tokenization of scientific assets and provides a strategy to extend the life of scientific assets even after laboratories or sources close.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"236 ","pages":"Article 116874"},"PeriodicalIF":5.3,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143673021","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"AMPK phosphorylation of KCa2.3 alleviates angiotensin II-induced endothelial dysfunction","authors":"Zheng-Da Pang ,&nbsp;Yan Wang ,&nbsp;Meng-Zhuan Han ,&nbsp;Gang She ,&nbsp;Xia Sun ,&nbsp;Ru-Yue Bai ,&nbsp;Bao-Chang Lai ,&nbsp;Yi Zhang ,&nbsp;Xiao-Jun Du ,&nbsp;John Y.-J. Shyy ,&nbsp;Xiu-Ling Deng","doi":"10.1016/j.bcp.2025.116880","DOIUrl":"10.1016/j.bcp.2025.116880","url":null,"abstract":"<div><div>The endothelial small-conductance calcium-activated potassium channels (K_Ca2.3) are indispensable for endothelium-dependent hyperpolarization (EDH) response, mainly in resistance arteries. We recently demonstrated in diet-induced obese mice that adenosine monophosphate-activated protein kinase (AMPK) upregulates endothelial K_Ca2.3 expression and improves endothelial function. However, the molecular mechanism of regulation of K_Ca2.3 by AMPK remains less explored. Using techniques of bioinformatics, molecular biology and wire myograph system, we examined K_Ca2.3 phosphorylation by AMPK in human umbilical vein endothelial cells (HUVECs), human embryonic kidney 293 (HEK-293T) cells and second-order mesenteric resistance arteries from angiotensin II-induced hypertensive mice. In HUVECs, treatment with activators of AMPK (AICAR, metformin, and MK-8722) significantly increased phosphorylation of K_Ca2.3 Thr106 (human), which was antagonized by AMPK inhibitor compound C. In HEK-293T cells, K_Ca2.3 current was enhanced by AMPK activation or phosphomimetic mutant K_Ca2.3 (T106D), which was abolished after de-phosphomimetic mutant (T106A) or deletion of K_Ca2.3 of Thr106 site (T106Del). In mice with angiotensin II infusion, 2-week treatment with AICAR or overexpressing phosphomimetic mutant K_Ca2.3 Thr107D (mouse) restored K_Ca2.3-mediated EDH-dependent relaxation in mesenteric resistance arteries together with reversal of early phase hypertension. Our study demonstrates for the first time that AMPK activation mediates K_Ca2.3 phosphorylation in endothelial cells with enhanced channel activity. This effect ameliorates endothelial dysfunction of mesenteric resistance arteries and alleviates angiotensin II-induced early phase hypertension in mice.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"236 ","pages":"Article 116880"},"PeriodicalIF":5.3,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143668990","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting RBM39 with Tasisulam enhances TRAIL-induced apoptosis through DR5 upregulation and Bcl-2 downregulation in renal cell carcinoma","authors":"Ji Hoon Jang ,&nbsp;Haein Kim ,&nbsp;Heejin Jun ,&nbsp;Cho-Young Park ,&nbsp;Joo-Young Kim ,&nbsp;Mirae Yeo ,&nbsp;Hunmin Kim ,&nbsp;Yerim Shin ,&nbsp;Sebyung Kang ,&nbsp;Eunhee Kim ,&nbsp;Tae-Jin Lee","doi":"10.1016/j.bcp.2025.116877","DOIUrl":"10.1016/j.bcp.2025.116877","url":null,"abstract":"<div><div>Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) selectively induces apoptosis in tumor cells but faces limitations due to resistance mechanisms involving anti-apoptotic regulators such as Bcl-2. This study investigates Tasisulam, a molecular glue degrader, that degrades RNA-binding motif protein 39 (RBM39), as a sensitizer for TRAIL-mediated apoptosis in renal cell carcinoma (RCC). Tasisulam enhances TRAIL-induced apoptosis by activating both extrinsic and intrinsic apoptotic pathways, achieved through upregulation of death receptor 5 (DR5) and downregulation of B-cell lymphoma 2 (Bcl-2). Importantly, Tasisulam selectively sensitizes RCC cells to TRAIL-induced apoptosis without affecting normal cells.<!--> <!-->RBM39 knockdown mimicked the effects of Tasisulam by upregulating DR5, downregulating Bcl-2, and enhancing TRAIL-induced apoptosis, suggesting RBM39 as a critical regulator of these pathways. To address TRAIL instability <em>in vivo</em>, AaLS/TRAIL nanoparticles were employed in combination with Tasisulam in a Caki-1 xenograft model. This combination significantly reduced tumor volume and weight compared to single treatments, without observed toxicity. These findings demonstrate that Tasisulam sensitizes RCC cells to TRAIL-induced apoptosis through RBM39-dependent DR5 upregulation and Bcl-2 downregulation. This combination strategy holds significant promise as a potential solution to overcoming TRAIL resistance and advancing more effective treatment outcomes for RCC.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"236 ","pages":"Article 116877"},"PeriodicalIF":5.3,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143669021","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"H1.0 modulates IL-6 expression and paclitaxel resistance via HDAC5 in ovarian cancer cells","authors":"Shang-Lang Huang ,&nbsp;Ting‐Chang Chang ,&nbsp;Nian-Kang Sun","doi":"10.1016/j.bcp.2025.116876","DOIUrl":"10.1016/j.bcp.2025.116876","url":null,"abstract":"<div><div>Chemoresistance is a significant challenge and major obstacle to achieving cancer remission during chemotherapy, primarily due to the risk of recurrence and metastasis. This study reveals that linker histone H1.0 plays a crucial role in paclitaxel resistance (TXR) in ovarian cancer cells by regulating Histone deacetylase 5 (HDAC5), which deacetylates core histones and represses gene transactivation. Transcriptomic profile analysis revealed that cytokine signaling networks are enriched pathways that correlate with H1.0 expression. Advanced clustering analysis identified interleukin 6 (IL-6) as a key molecule connecting these enriched H1.0-related pathways. Furthermore, gain- and loss-of-H1.0 expression experiments showed that H1.0 controls IL-6 mRNA and protein expression in ovarian cancer cells. Additionally, our findings indicate that HDAC5 expression is downregulated in SKOV3/Txr cells compared with parental cells. H1.0 silencing in TXR cells increases HDAC5 levels, suggesting an antagonistic effect between H1.0 and HDAC5. Cell viability assays showed that HDAC5 overexpression markedly inhibited cell survival. Furthermore, ectopic HDAC5 overexpression reduced IL-6 mRNA and protein expression, which was increased by H1.0. This effect was associated with reduced H3K9Ac core histone acetylation and decreased NF-κB binding on the IL-6 promoter, as demonstrated by chromatin immunoprecipitation assays. Further analysis revealed that HDAC5 is downregulated in several tumor types. Furthermore, high H1.0 and IL-6 expression, coupled with low HDAC5 levels, was exclusively observed in ovarian carcinoma. Together, our results demonstrate an interplay between H1.0, HDAC5, and IL-6 in modulating paclitaxel resistance in ovarian cancer cells, highlighting new therapeutic targets to overcome chemoresistance.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"236 ","pages":"Article 116876"},"PeriodicalIF":5.3,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143668991","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ivabradine ameliorates doxorubicin-induced cardiotoxicity through improving mitochondrial function and cardiac calcium homeostasis","authors":"Adivitch Sripusanapan ,&nbsp;Chotrawee Piriyakulthorn ,&nbsp;Nattayaporn Apaijai ,&nbsp;Siriporn C. Chattipakorn ,&nbsp;Nipon Chattipakorn","doi":"10.1016/j.bcp.2025.116881","DOIUrl":"10.1016/j.bcp.2025.116881","url":null,"abstract":"<div><div>Doxorubicin (Dox) is a potent anthracycline chemotherapeutic agent. However, its efficacy is limited by its cardiotoxicity, which is driven by excessive oxidative stress, calcium overload, and mitochondrial dysfunction. These mechanisms ultimately result in cardiomyocyte death and cardiac dysfunction. Ivabradine, a hyperpolarization-activated cyclic nucleotide-gated channel blocker, has cardioprotective effects in heart failure and coronary artery disease. However, its potential for mitigating doxorubicin-induced cardiotoxicity (DIC) has not been explored. This study hypothesized that ivabradine reduces cardiac dysfunction in DIC by improving mitochondrial function, restoring calcium homeostasis, and attenuating apoptosis. For <em>in vitro</em> experiments, H9C2 cells were divided into four groups: control, ivabradine (3 μM), Dox (10 μM), and ivabradine co-treated with Dox, with treatments lasting 24 h. Cell viability and mitochondrial function were assessed. For <em>in vivo</em> experiments, male rats (n = 6 per group) were divided into control, ivabradine (10 mg/kg/day, p.o., 30 days), Dox (3 mg/kg, i.p., 6 doses), and ivabradine co-treated with Dox. Cardiac function, mitochondrial function, calcium regulatory proteins, and apoptosis were analyzed. Dox reduced cell viability, increased oxidative stress, and decreased ATP levels <em>in vitro</em>. Co-treatment with ivabradine increased cell viability and reduced oxidative stress but did not restore ATP levels. In rats, Dox impaired mitochondrial function, disrupted mitochondrial dynamics and mitophagy, and altered calcium homeostasis, resulting in cardiomyocyte apoptosis and left ventricular dysfunction. Ivabradine co-treatment attenuated these pathological changes and preserved cardiac function. These findings suggest the potential of ivabradine for cardioprotection against DIC.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"236 ","pages":"Article 116881"},"PeriodicalIF":5.3,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143668995","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Loss of aryl hydrocarbon receptor reduces pancreatic tumor growth by increasing immune cell infiltration","authors":"Vinicius Kannen ,&nbsp;Ninni E. Olafsen ,&nbsp;Siddhartha Das ,&nbsp;Paolo Giuliana ,&nbsp;Fauzia N. Izzati ,&nbsp;Hani Choksi ,&nbsp;Samaneh S. Åhrling ,&nbsp;Paola Cappello ,&nbsp;Indrek Teino ,&nbsp;Toivo Maimets ,&nbsp;Kristaps Jaudzems ,&nbsp;Antanas Gulbinas ,&nbsp;Zilvinas Dambrauskas ,&nbsp;Landon J. Edgar ,&nbsp;Denis M. Grant ,&nbsp;Jason Matthews","doi":"10.1016/j.bcp.2025.116872","DOIUrl":"10.1016/j.bcp.2025.116872","url":null,"abstract":"<div><div>Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease which remains poorly understood. Increasing evidence suggests that the aryl hydrocarbon receptor (AHR) plays a role in the pathogenesis of several cancers; however, its role in PDAC is unclear because AHR exhibits both pro- and anti-tumor activities. Here we evaluated the role of AHR in CR705 and K8484 murine PDAC cells <em>in vitro</em> and CR705 cells <em>in vivo</em>. Loss of <em>Ahr</em> did not affect cell proliferation compared with Cas9 control cells and no differences in tumor development between CR705^Cas9 and CR705^AhrKO cells were observed in immunocompromised mice. Conversely, tumors from CR705^AhrKO cells grew more slowly than tumors from CR705^Cas9 cells in immune competent mice. RNA sequencing identified 1279 genes upregulated and 586 genes downregulated in CR705^AhrKO tumors compared with CR705^Cas9 tumors. Pathway analysis identified immunoregulatory interactions, interferon signaling, and chemokine signaling among the top upregulated pathways. Increased infiltration of CD45⁺ cells and higher numbers of CD8⁺ T cells and F4/80⁺ cells were observed in CR705^AhrKO tumors. <em>Ahr</em> deficiency in macrophages (LysMCre) or lymphocytes (RorcCre) did not alter tumor development of CR705^Cas9 cells compared with <em>Ahr^fl/fl</em> mice. CR705^AhrKO tumors in RorcCre mice, but not in LysMCre mice had significantly lower tumor weights normalized to body weights compared with CR705^AhrKO tumors in WT mice. These findings show that <em>Ahr</em> loss in CR705 pancreatic cancer cells is sufficient to induce proinflammatory gene responses that contribute to increased immune cell infiltration and reduced tumor growth.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"236 ","pages":"Article 116872"},"PeriodicalIF":5.3,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143639513","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}