Cell Communication and Signaling最新文献

{"title":"Regulation of ADAM10 activity through microdomain-dependent intracellular calcium changes.","authors":"Federico Guillermo Gharzia, Ahmad Aljohmani, Andreas Beck, Stephan E Philipp, Daniela Yildiz","doi":"10.1186/s12964-024-01891-5","DOIUrl":"10.1186/s12964-024-01891-5","url":null,"abstract":"<p><p>A disintegrin and metalloproteinases (ADAMs) are transmembrane proteases that cleave other proteins close to the surface in a process called shedding. The prominent member ADAM10 has been linked to several pathologies such as Alzheimer's disease, bacterial infection, cancer development and metastasis. Although the regulation of the ADAM10 activity by calcium influx and calmodulin inhibition has been reported, the spatiotemporal regulation of Ca²⁺-dependent ADAM10 activation and the required source of Ca²⁺ ions have not been thoroughly studied. In the present study, we observed the rapid Ca²⁺-dependent activation of ADAM10 in A549 lung carcinoma cells upon stimulation with ionomycin. The calmodulin-inhibitors trifluoperazine and ophiobolin A mediated delayed activation of ADAM10, which apparently did not depend on intracellular Ca²⁺ in the case of trifluoperazine. Furthermore, the surface translocation and release of ADAM10 in extracellular vesicles exhibited different kinetics and were only partially linked to catalytic activation. Finally, ADAM10 activation was observed after the entry of Ca²⁺ through certain channels, such as canonical members of transient receptor potential (TRP) channels. Therefore, the opening of particular channels for Ca²⁺ entry points and subsequent Ca²⁺ flux as well as the temporal aspects of the consequent increase in Ca²⁺ levels, must be considered for future therapeutic options involving the increasing or decreasing ADAM10 activity.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"22 1","pages":"531"},"PeriodicalIF":8.2,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11533308/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142577158","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Blue light-driven cell cycle arrest in thyroid cancer via Retinal-OPN3 complex.","authors":"Changrui Zhao, Jiaqiang Bo, Tianyu Li, Jiameng Tian, Tian Long, Yingying He, Siyu Chen, Chang Liu","doi":"10.1186/s12964-024-01908-z","DOIUrl":"10.1186/s12964-024-01908-z","url":null,"abstract":"<p><strong>Background: </strong>Papillary thyroid carcinoma (PTC) is the most common type of thyroid malignancy, with a rising incidence. Traditional treatments, such as thyroidectomy and radiotherapy, often lead to significant side effects, including impaired thyroid function. Therefore, there is an urgent need for non-invasive therapeutic approaches. This study aims to explore the potential of photobiomodulation therapy (PBMT), a non-invasive treatment using specific wavelengths of light, in the management of PTC.</p><p><strong>Methods: </strong>We investigated the effects of blue light PBMT on PTC cells, focusing on the Retinal-OPSIN 3 (OPN3) complex's role in mediating cellular responses. Blue light exposure was applied to PTC cells, and subsequent changes in cellular proliferation, cell cycle progression, and protein expression were analyzed. Statistical tests, including one-way ANOVA and t-tests, were used to evaluate the significance of the findings.</p><p><strong>Results: </strong>Blue light exposure led to the dissociation of 11-cis-retinal from OPN3, resulting in the accumulation of all-trans retinal. This accumulation disrupted cellular proliferation pathways and induced G0/G1 cell cycle arrest in PTC cells. The Retinal-OPN3 complex was found to be a key mediator in these processes, demonstrating that thyroid cells can respond to specific light wavelengths and utilize their photoreceptive potential for therapeutic purposes.</p><p><strong>Conclusions: </strong>Our findings suggest that PBMT, through the modulation of the Retinal-OPN3 complex, offers a promising non-invasive approach for treating PTC. This study highlights the therapeutic potential of light signal transduction in non-ocular tissues and opens new avenues for non-invasive cancer therapies.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"22 1","pages":"530"},"PeriodicalIF":8.2,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11531186/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142565096","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PIM1 kinase and its diverse substrate in solid tumors.","authors":"Rituparna Choudhury, Chandan Kumar Bahadi, Ipsa Pratibimbita Ray, Pragyanshree Dash, Isha Pattanaik, Suman Mishra, Soumya R Mohapatra, Srinivas Patnaik, Kumar Nikhil","doi":"10.1186/s12964-024-01898-y","DOIUrl":"10.1186/s12964-024-01898-y","url":null,"abstract":"<p><p>The PIM kinase family, consisting of PIM1, PIM2, and PIM3, is a group of serine/threonine protein kinases crucial for cellular growth, immunoregulation, and oncogenesis. PIM1 kinase is often overexpressed in solid and hematopoietic malignancies, promoting cell survival, proliferation, migration, and senescence by activating key genes. In vitro and in vivo studies have established the oncogenic potential of PIM1 kinases. These kinases have been implicated in tumor progression, metastasis, and resistance to chemotherapy, underscoring their potential as a therapeutic target for cancer therapy. This review delves into the intricate molecular mechanisms through which PIM1 interacts with specific substrates in different tumor tissues, leading to diverse outcomes in various human cancers. Over the past decade, the inhibition of PIM1 in cancers has garnered significant attention as a potential standalone treatment. Various in vitro, in vivo, and early clinical trial data have provided support for this approach to varying extents. Novel compounds that inhibit PIM1 kinase have shown effectiveness and a favorable toxicity profile in preclinical studies. Several of these substances are now being studied in clinical trials due to their promising outcomes. This article provides a thorough examination of the PIM1 kinase pathways and the recent advancements in producing PIM1 kinase inhibitors for the treatment of cancer.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"22 1","pages":"529"},"PeriodicalIF":8.2,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11531143/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142565098","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exosome-based immunotherapy as an innovative therapeutic approach in melanoma.","authors":"Shabnam Babaei, Manouchehr Fadaee, Hajar Abbasi-Kenarsari, Dariush Shanehbandi, Tohid Kazemi","doi":"10.1186/s12964-024-01906-1","DOIUrl":"10.1186/s12964-024-01906-1","url":null,"abstract":"<p><p>The malignant form of melanoma is one of the deadliest human cancers that accounts for almost all of the skin tumor-related fatalities in its later stages. Achieving an exhaustive understanding of reliable cancer-specific markers and molecular pathways can provide numerous practical techniques and direct the way toward the development of rational curative medicines to increase the lifespan of patients. Immunotherapy has significantly enhanced the treatment of metastatic and late-stage melanoma, resulting in an incredible increase in positive responses to therapy. Despite the increasing occurrence of melanoma, the median survival rate for patients with advanced, inoperable terminal disease has increased from around six months to almost six years. The current knowledge of the tumor microenvironment (TME) and its interaction with the immune system has resulted in the swift growth of innovative immunotherapy treatments. Exosomes are small extracellular vesicles (EVs), ranging from 30 to 150 nm in size, that the majority of cells released them. Exosomes possess natural advantages such as high compatibility with living organisms and low potential for causing immune reactions, making them practical for delivering therapeutic agents like chemotherapy drugs, nucleic acids, and proteins. This review highlights recent advancements in using exosomes as an approach to providing medications for the treatment of melanoma.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"22 1","pages":"527"},"PeriodicalIF":8.2,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11526674/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142559519","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Refractory testicular germ cell tumors are highly sensitive to the targeting of polycomb pathway demethylases KDM6A and KDM6B.","authors":"Doha Shokry, Mehwish W Khan, Christine Powell, Samantha Johnson, Brayden C Rennels, Raya I Boyd, Zhengyang Sun, Zeeshan Fazal, Sarah J Freemantle, Maryanna H Parker, Miranda D Vieson, Jonathan P Samuelson, Michael J Spinella, Ratnakar Singh","doi":"10.1186/s12964-024-01912-3","DOIUrl":"10.1186/s12964-024-01912-3","url":null,"abstract":"<p><p>Testicular germ cell tumors (TGCTs) can be treated with cisplatin-based therapy. However, a clinically significant number of cisplatin-resistant patients die from progressive disease as no effective alternatives exist. Curative cisplatin therapy results in acute and life-long toxicities in the young TGCT patient population providing a rationale to decrease cisplatin exposure. In contrast to genetic alterations, recent evidence suggests that epigenetics is a major driving factor for TGCT formation, progression, and response to chemotherapy. Hence, targeting epigenetic pathways with \"epidrugs\" is one potential relatively unexplored strategy to advance TGCT treatment beyond cisplatin. In this report, we demonstrate for the first time that targeting polycomb demethylases KDM6A and KDM6B with epidrug GSK-J4 can treat both cisplatin-sensitive and -resistant TGCTs. While GSK-J4 had minimal effects alone on TGCT tumor growth in vivo, it dramatically sensitized cisplatin-sensitive and -resistant TGCTs to cisplatin. We validated KDM6A/KDM6B as the target of GSK-J4 since KDM6A/KDM6B genetic depletion had a similar effect to GSK-J4 on cisplatin-mediated anti-tumor activity and transcriptome alterations. Pharmacologic and genetic targeting of KDM6A/KDM6B potentiated or primed the p53-dominant transcriptional response to cisplatin, with also evidence for basal activation of p53. Further, several chromatin modifier genes, including BRD4, lysine demethylases, chromodomain helicase DNA binding proteins, and lysine methyltransferases, were repressed with cisplatin only in KDM6A/KDM6B-targeted cells, implying that KDM6A/KDM6B inhibition sets the stage for extensive chromatin remodeling of TGCT cells upon cisplatin treatment. Our findings demonstrate that targeting polycomb demethylases is a new potent pharmacologic strategy for treating cisplatin resistant TGCTs that warrants clinical development.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"22 1","pages":"528"},"PeriodicalIF":8.2,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11529429/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142559520","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A non-catalytic role of IPMK is required for PLCγ1 activation in T cell receptor signaling by stabilizing the PLCγ1-Sam68 complex.","authors":"Sehoon Hong, Kyurae Kim, Young-Ri Shim, Jiyeon Park, Sung Eun Choi, Hyungyu Min, Seulgi Lee, Ji-Joon Song, Suk-Jo Kang, Won-Il Jeong, Rho Hyun Seong, Seyun Kim","doi":"10.1186/s12964-024-01907-0","DOIUrl":"10.1186/s12964-024-01907-0","url":null,"abstract":"<p><strong>Background: </strong>Phospholipase C gamma 1 (PLCγ1) is an important mediator of the T cell receptor (TCR) and growth factor signaling. PLCγ1 is activated by Src family kinases (SFKs) and produces inositol 1,4,5-triphosphate (InsP₃) from phosphatidylinositol 4,5-bisphosphate (PIP₂). Inositol polyphosphate multikinase (IPMK) is a pleiotropic enzyme with broad substrate specificity and non-catalytic activities that mediate various functional protein-protein interactions. Therefore, IPMK plays critical functions in key biological events such as cell growth. However, the contribution of IPMK to the activation of PLCγ1 in TCR signaling remains mostly unelucidated. The current study aimed to elucidate the functions of IPMK in TCR signaling and to uncover the mode of IPMK-mediated signaling action in PLCγ1 activation.</p><p><strong>Methods: </strong>Concanavalin A (ConA)-induced acute hepatitis model was established in CD4⁺ T cell-specific IPMK knockout mice (IPMK^ΔCD4). Histological analysis was performed to assess hepatic injury. Primary cultures of naïve CD4⁺ T cells were used to uncover the role of mechanisms of IPMK in vitro. Western blot analysis, quantitative real-time PCR, and flow cytometry were performed to analyze the TCR-stimulation-induced PLCγ1 activation and the downstream signaling pathway in naïve CD4⁺ T cells. Yeast two-hybrid screening and co-immunoprecipitation were conducted to identify the IPMK-binding proteins and protein complexes.</p><p><strong>Results: </strong>IPMK^ΔCD4 mice showed alleviated ConA-induced acute hepatitis. CD4⁺ helper T cells in these mice showed reduced PLCγ1 Y783 phosphorylation, which subsequently dampens calcium signaling and IL-2 production. IPMK was found to contribute to PLCγ1 activation via the direct binding of IPMK to Src-associated substrate during mitosis of 68 kDa (Sam68). Mechanistically, IPMK stabilizes the interaction between Sam68 and to PLCγ1, thereby promoting PLCγ1 phosphorylation. Interfering this IPMK-Sam68 binding interaction with IPMK dominant-negative peptides impaired PLCγ1 phosphorylation.</p><p><strong>Conclusions: </strong>Our results demonstrate that IPMK non-catalytically promotes PLCγ1 phosphorylation by stabilizing the PLCγ1-Sam68 complex. Targeting IPMK in CD4⁺ T cells may be a promising strategy for managing immune diseases caused by excessive stimulation of TCR.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"22 1","pages":"526"},"PeriodicalIF":8.2,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11524019/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142549043","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The multifaceted role of mitochondria in cardiac function: insights and approaches.","authors":"Sriram Ravindran, Christoph D Rau","doi":"10.1186/s12964-024-01899-x","DOIUrl":"10.1186/s12964-024-01899-x","url":null,"abstract":"<p><p>Cardiovascular disease (CVD) remains a global economic burden even in the 21st century with 85% of deaths resulting from heart attacks. Despite efforts in reducing the risk factors, and enhancing pharmacotherapeutic strategies, challenges persist in early identification of disease progression and functional recovery of damaged hearts. Targeting mitochondrial dysfunction, a key player in the pathogenesis of CVD has been less successful due to its role in other coexisting diseases. Additionally, it is the only organelle with an agathokakological function that is a remedy and a poison for the cell. In this review, we describe the origins of cardiac mitochondria and the role of heteroplasmy and mitochondrial subpopulations namely the interfibrillar, subsarcolemmal, perinuclear, and intranuclear mitochondria in maintaining cardiac function and in disease-associated remodeling. The cumulative evidence of mitochondrial retrograde communication with the nucleus is addressed, highlighting the need to study the genotype-phenotype relationships of specific organelle functions with CVD by using approaches like genome-wide association study (GWAS). Finally, we discuss the practicality of computational methods combined with single-cell sequencing technologies to address the challenges of genetic screening in the identification of heteroplasmy and contributory genes towards CVD.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"22 1","pages":"525"},"PeriodicalIF":8.2,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11523909/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142549045","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Gelsolin regulates intestinal stem cell regeneration and Th17 cellular function.","authors":"Jicong Du, Lan Fang, Yuedong Wang, Jianpeng Zhao, Zhenlan Feng, Yike Yu, Duo Fang, Daqian Huang, Xuanlu Zhai, Ying Cheng, Rui Min, Fu Gao, Cong Liu","doi":"10.1186/s12964-024-01902-5","DOIUrl":"10.1186/s12964-024-01902-5","url":null,"abstract":"<p><p>Intestinal stem cells (ISCs) are responsible for intestinal homeostasis and are important for the regeneration of damaged intestine. We established an ionizing radiation (IR)-induced intestinal injury model and observed that Gelsolin KO mice had increased radiosensitivity. The deletion of Gelsolin aggravated intestinal damage and reduced the number of ISCs after lethal IR. The intestinal organoid experiments showed that Gelsolin deletion inhibited ISCs function after IR. Notably, RNA sequencing and RT-PCR results showed IL-17 signaling pathway was down-regulated and Th17 cells differentiation was inhibited in Gelsolin KO mice. Moreover, recombinant IL-17 A ameliorated IR-induced intestinal injury and promoted ISCs regeneration. To figure out the role of Gelsolin in Th17 cells differentiation, flow cytometry was used and we found that Gelsolin targets Th17 cells functionality via the p-STAT3/RORγt axis. By establishing the co-culture system, we proved that Th17 cells promoted self-renewal and budding abilities in Gelsolin-deficient organoids. Finally, we found that Gelsolin was protective against DSS-induced colitis and that this protective effect was not specific or limited to the IR induced intestinal injury model. Based on these results, we proved Gelsolin maintained the regeneration of ISCs by sustaining Th17 cells functions via the p-STAT3/RORγt axis.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"22 1","pages":"524"},"PeriodicalIF":8.2,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11520831/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142549044","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Septins as key players in spermatogenesis, fertilisation and pre-implantation embryogenic cytoplasmic dynamics.","authors":"Hana Al-Ali, Amna Baig, Rayyah R Alkhanjari, Zoha F Murtaza, Maitha M Alhajeri, Rawdah Elbahrawi, Azhar Abdukadir, Poorna Manasa Bhamidimarri, Junaid Kashir, Hamdan Hamdan","doi":"10.1186/s12964-024-01889-z","DOIUrl":"10.1186/s12964-024-01889-z","url":null,"abstract":"<p><p>Septins are a family of cytokinesis-related proteins involved in regulating cytoskeletal design, cell morphology, and tissue morphogenesis. Apart from cytokinesis, as a fourth component of cytoskeleton, septins aid in forming scaffolds, vesicle sorting and membrane stability. They are also known to be involved in the regulation of intracellular calcium (Ca²⁺) via the STIM/Orai complex. Infertility affects ~ 15% of couples globally, while male infertility affects ~ 7% of men. Global pregnancy and live birth rates following fertility treatment remain relatively low, while there has been an observable decline in male fertility parameters over the past 60 years. Low fertility treatment success can be attributed to poor embryonic development, poor sperm parameters and fertilisation defects. While studies from the past few years have provided evidence for the role of septins in fertility related processes, the functional role of septins and its related complexes in cellular processes such as oocyte activation, fertilization, and sperm maturation are not completely understood. This review summarizes the available knowledge on the role of septins in spermatogenesis and oocyte activation via Ca²⁺ regulation, and cytoskeletal dynamics throughout pre-implantation embryonic development. We aim to identify the currently less known mechanisms by which septins regulate these immensely important mechanisms with a view of identifying areas of investigation that would benefit our understanding of cell and reproductive biology, but also provide potential avenues to improve current methods of fertility treatment.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"22 1","pages":"523"},"PeriodicalIF":8.2,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11514797/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142523673","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transcriptional responses to direct and indirect TGFB1 stimulation in cancerous and noncancerous mammary epithelial cells.","authors":"Patryk Janus, Paweł Kuś, Roman Jaksik, Natalia Vydra, Agnieszka Toma-Jonik, Michalina Gramatyka, Monika Kurpas, Marek Kimmel, Wiesława Widłak","doi":"10.1186/s12964-024-01821-5","DOIUrl":"10.1186/s12964-024-01821-5","url":null,"abstract":"<p><strong>Background: </strong>Transforming growth factor beta (TGFβ) is important for the morphogenesis and secretory function of the mammary gland. It is one of the main activators of the epithelial-mesenchymal transition (EMT), a process important for tissue remodeling and regeneration. It also provides cells with the plasticity to form metastases during tumor progression. Noncancerous and cancer cells respond differently to TGFβ. However, knowledge of the cellular signaling cascades triggered by TGFβ in various cell types is still limited.</p><p><strong>Methods: </strong>MCF10A (noncancerous, originating from fibrotic breast tissue) and MCF7 (cancer, estrogen receptor-positive) breast epithelial cells were treated with TGFB1 directly or through conditioned media from stimulated cells. Transcriptional changes (via RNA-seq) were assessed in untreated cells and after 1-6 days of treatment. Differentially expressed genes were detected with DESeq2 and the hallmark collection was selected for gene set enrichment analysis.</p><p><strong>Results: </strong>TGFB1 induces EMT in both the MCF10A and MCF7 cell lines but via slightly different mechanisms (signaling through SMAD3 is more active in MCF7 cells). Many EMT-related genes are expressed in MCF10A cells at baseline. Both cell lines respond to TGFB1 by decreasing the expression of genes involved in cell proliferation: through the repression of MYC (and the protein targets) in MCF10A cells and the activation of p63-dependent signaling in MCF7 cells (CDKN1A and CDKN2B, which are responsible for the inhibition of cyclin-dependent kinases, are upregulated). In addition, estrogen receptor signaling is inhibited and caspase-dependent cell death is induced only in MCF7 cells. Direct incubation with TGFB1 and treatment of cells with conditioned media similarly affected transcriptional profiles. However, TGFB1-induced protein secretion is more pronounced in MCF10A cells; therefore, the signaling is propagated through conditioned media (bystander effect) more effectively in MCF10A cells than in MCF7 cells.</p><p><strong>Conclusions: </strong>Estrogen receptor-positive breast cancer patients may benefit from high levels of TGFB1 expression due to the repression of estrogen receptor signaling, inhibition of proliferation, and induction of apoptosis in cancer cells. However, some TGFB1-stimulated cells may undergo EMT, which increases the risk of metastasis.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"22 1","pages":"522"},"PeriodicalIF":8.2,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11514872/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142523674","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}