Journal of Biomedical Science最新文献

{"title":"Variants of human DECTIN-1 rs16910526 are linked to differential reactive oxygen species production and susceptibility to tuberculosis.","authors":"Mónica Cufré, Mercedes Pastorini, Ignacio Martín, Rodrigo Failde, Domingo Palmero, Mercedes Alemán","doi":"10.1186/s12929-024-01067-w","DOIUrl":"10.1186/s12929-024-01067-w","url":null,"abstract":"<p><strong>Background: </strong>Dectin-1 is a transmembrane receptor that plays a pivotal role in recognising fungi and Mycobacterium tuberculosis (Mtb). A specific variant, DECTIN-1 rs16910526, results in a truncated receptor that disrupts membrane expression and ligand binding and is clinically associated with recurrent cutaneous mycoses. Previous research has clarified the role of Dectin-1 in boosting immune defenses against mycobacteria by enhancing reactive oxygen species (ROS) production in neutrophils (PMNs). Here, we investigated the association between the rs16910526 variant and Dectin-1 expression in PMNs, as well as intracellular ROS production in response to Mtb. Furthermore, we explored the potential link between the rs16910526 gene variant and TB outcomes in Argentina.</p><p><strong>Methods: </strong>DNA was extracted from blood samples obtained from a cohort of 178 TB patients and healthy subjects (HS) in Argentina. PCR amplification and sequencing were performed to identify the rs16910526 variant. Flow cytometry was utilised to assess Dectin-1 expression on the PMN plasma membrane and to measure intracellular ROS levels, as indicated by the oxidation of DHR123 in response to the Mtb antigen.</p><p><strong>Results: </strong>PMNs carrying the rs16910526 variant exhibited diminished Dectin-1 expression and ROS production in response to Mtb (p < 0.0001). In a case‒control study, the rs16910526 variant had an allelic frequency of 0.112 in TB patients and 0.051 in HS. Notably, 10 out of 88 HS and 18 out of 62 TB patients harboured the variant (odds ratio [OR]: 2.55 [95% CI 1.1-5.9, p = 0.03]), indicating a potential association with TB disease. Furthermore, TB patients with the rs16910526 variant exhibited a delayed sputum smear conversion time (p < 0.004) and 100% positivity for acid-fast bacilli smears (p < 0.00001).</p><p><strong>Conclusion: </strong>Our study identified a significant association between the SNP variant rs16910526 in the DECTIN-1 gene and Dectin-1 expression in the PMN, leading to altered ROS production. The higher frequency of this variant in TB patients compared to HS suggests a possible link with susceptibility to TB disease in Argentina.</p>","PeriodicalId":15365,"journal":{"name":"Journal of Biomedical Science","volume":"31 1","pages":"77"},"PeriodicalIF":9.0,"publicationDate":"2024-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11302830/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141893509","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":"Retraction Note: Inhibitors of apoptosis proteins in experimental benign prostatic hyperplasia: effects of Serenoa repens, selenium and lycopene.","authors":"Letteria Minutoli, Domenica Altavilla, Herbert Marini, Mariagrazia Rinaldi, Natasha Irrera, Gabriele Pizzino, Alessandra Bitto, Salvatore Arena, Sebastiano Cimino, Francesco Squadrito, Giorgio Ivan Russo, Giuseppe Morgia","doi":"10.1186/s12929-024-01066-x","DOIUrl":"10.1186/s12929-024-01066-x","url":null,"abstract":"","PeriodicalId":15365,"journal":{"name":"Journal of Biomedical Science","volume":"31 1","pages":"76"},"PeriodicalIF":9.0,"publicationDate":"2024-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11295897/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141878770","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":"Development of novel antimicrobials with engineered endolysin LysECD7-SMAP to combat Gram-negative bacterial infections.","authors":"Daria V Vasina, Nataliia P Antonova, Vladimir A Gushchin, Andrey V Aleshkin, Mikhail V Fursov, Anastasiia D Fursova, Petya G Gancheva, Igor V Grigoriev, Pavel Grinkevich, Alexey V Kondratev, Alexey V Kostarnoy, Anastasiya M Lendel, Valentine V Makarov, Maria A Nikiforova, Andrei A Pochtovyi, Tatiana Prudnikova, Timofey A Remizov, Natalia V Shevlyagina, Andrei E Siniavin, Nina S Smirnova, Alexander A Terechov, Artem P Tkachuk, Evgeny V Usachev, Aleksei M Vorobev, Victoria S Yakimakha, Sergey M Yudin, Anastasia A Zackharova, Vladimir G Zhukhovitsky, Denis Y Logunov, Alexander L Gintsburg","doi":"10.1186/s12929-024-01065-y","DOIUrl":"10.1186/s12929-024-01065-y","url":null,"abstract":"<p><strong>Background: </strong>Among the non-traditional antibacterial agents in development, only a few targets critical Gram-negative bacteria such as carbapenem-resistant Pseudomonas aeruginosa, Acinetobacter baumannii or cephalosporin-resistant Enterobacteriaceae. Endolysins and their genetically modified versions meet the World Health Organization criteria for innovation, have a novel mode of antibacterial action, no known bacterial cross-resistance, and are being intensively studied for application against Gram-negative pathogens.</p><p><strong>Methods: </strong>The study presents a multidisciplinary approach, including genetic engineering of LysECD7-SMAP and production of recombinant endolysin, its analysis by crystal structure solution following molecular dynamics simulations and evaluation of antibacterial properties. Two types of antimicrobial dosage forms were formulated, resulting in lyophilized powder for injection and hydroxyethylcellulose gel for topical administration. Their efficacy was estimated in the treatment of sepsis, and pneumonia models in BALB/c mice, diabetes-associated wound infection in the leptin receptor-deficient db/db mice and infected burn wounds in rats.</p><p><strong>Results: </strong>In this work, we investigate the application strategies of the engineered endolysin LysECD7-SMAP and its dosage forms evaluated in preclinical studies. The catalytic domain of the enzyme shares the conserved structure of endopeptidases containing a putative antimicrobial peptide at the C-terminus of polypeptide chain. The activity of endolysins has been demonstrated against a range of pathogens, such as Klebsiella pneumoniae, A. baumannii, P. aeruginosa, Staphylococcus haemolyticus, Achromobacter spp, Burkholderia cepacia complex and Haemophylus influenzae, including those with multidrug resistance. The efficacy of candidate dosage forms has been confirmed in in vivo studies. Some aspects of the interaction of LysECD7-SMAP with cell wall molecular targets are also discussed.</p><p><strong>Conclusions: </strong>Our studies demonstrate the potential of LysECD7-SMAP therapeutics for the systemic or topical treatment of infectious diseases caused by susceptible Gram-negative bacterial species and are critical to proceed LysECD7-SMAP-based antimicrobials trials to advanced stages.</p>","PeriodicalId":15365,"journal":{"name":"Journal of Biomedical Science","volume":"31 1","pages":"75"},"PeriodicalIF":9.0,"publicationDate":"2024-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11267749/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141751818","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":"BUB1B monoallelic germline variants contribute to prostate cancer predisposition by triggering chromosomal instability.","authors":"Maria P Silva, Luísa T Ferreira, Natércia F Brás, Lurdes Torres, Andreia Brandão, Manuela Pinheiro, Marta Cardoso, Adriana Resende, Joana Vieira, Carlos Palmeira, Gabriela Martins, Miguel Silva, Carla Pinto, Ana Peixoto, João Silva, Rui Henrique, Sofia Maia, Helder Maiato, Manuel R Teixeira, Paula Paulo","doi":"10.1186/s12929-024-01056-z","DOIUrl":"10.1186/s12929-024-01056-z","url":null,"abstract":"<p><strong>Background: </strong>Prostate cancer (PrCa) is the most frequently diagnosed cancer in men. Variants in known moderate- to high-penetrance genes explain less than 5% of the cases arising at early-onset (< 56 years) and/or with familial aggregation of the disease. Considering that BubR1 is an essential component of the mitotic spindle assembly checkpoint, we hypothesized that monoallelic BUB1B variants could be sufficient to fuel chromosomal instability (CIN), potentially triggering (prostate) carcinogenesis.</p><p><strong>Methods: </strong>To unveil BUB1B as a new PrCa predisposing gene, we performed targeted next-generation sequencing in germline DNA from 462 early-onset/familial PrCa patients and 1,416 cancer patients fulfilling criteria for genetic testing for other hereditary cancer syndromes. To explore the pan-cancer role of BUB1B, we used in silico BubR1 molecular modeling, in vitro gene-editing, and ex vivo patients' tumors and peripheral blood lymphocytes.</p><p><strong>Results: </strong>Rare BUB1B variants were found in ~ 1.9% of the early-onset/familial PrCa cases and in ~ 0.6% of other cancer patients fulfilling criteria for hereditary disease. We further show that BUB1B variants lead to decreased BubR1 expression and/or stability, which promotes increased premature chromatid separation and, consequently, triggers CIN, driving resistance to Taxol-based therapies.</p><p><strong>Conclusions: </strong>Our study shows that different BUB1B variants may uncover a trigger for CIN-driven carcinogenesis, supporting the role of BUB1B as a (pan)-cancer predisposing gene with potential impact on genetic counseling and treatment decision-making.</p>","PeriodicalId":15365,"journal":{"name":"Journal of Biomedical Science","volume":"31 1","pages":"74"},"PeriodicalIF":9.0,"publicationDate":"2024-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11251299/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141626869","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":"Unraveling the differential mechanisms of revascularization promoted by MSCs & ECFCs from adipose tissue or umbilical cord in a murine model of critical limb-threatening ischemia.","authors":"Marta Rojas-Torres, Lucía Beltrán-Camacho, Ana Martínez-Val, Ismael Sánchez-Gomar, Sara Eslava-Alcón, Antonio Rosal-Vela, Margarita Jiménez-Palomares, Esther Doiz-Artázcoz, Mario Martínez-Torija, Rafael Moreno-Luna, Jesper V Olsen, Ma Carmen Duran-Ruiz","doi":"10.1186/s12929-024-01059-w","DOIUrl":"10.1186/s12929-024-01059-w","url":null,"abstract":"<p><strong>Background: </strong>Critical limb-threatening ischemia (CLTI) constitutes the most severe manifestation of peripheral artery disease, usually induced by atherosclerosis. CLTI patients suffer from high risk of amputation of the lower extremities and elevated mortality rates, while they have low options for surgical revascularization due to associated comorbidities. Alternatively, cell-based therapeutic strategies represent an effective and safe approach to promote revascularization. However, the variability seen in several factors such as cell combinations or doses applied, have limited their success in clinical trials, being necessary to reach a consensus regarding the optimal \"cellular-cocktail\" prior further application into the clinic. To achieve so, it is essential to understand the mechanisms by which these cells exert their regenerative properties. Herein, we have evaluated, for the first time, the regenerative and vasculogenic potential of a combination of endothelial colony forming cells (ECFCs) and mesenchymal stem cells (MSCs) isolated from adipose-tissue (AT), compared with ECFCs from umbilical cord blood (CB-ECFCs) and AT-MSCs, in a murine model of CLTI.</p><p><strong>Methods: </strong>Balb-c nude mice (n:32) were distributed in four different groups (n:8/group): control shams, and ischemic mice (after femoral ligation) that received 50 µl of physiological serum alone or a cellular combination of AT-MSCs with either CB-ECFCs or AT-ECFCs. Follow-up of blood flow reperfusion and ischemic symptoms was carried out for 21 days, when mice were sacrificed to evaluate vascular density formation. Moreover, the long-term molecular changes in response to CLTI and both cell combinations were analyzed in a proteomic quantitative approach.</p><p><strong>Results: </strong>AT-MSCs with either AT- or CB-ECFCs, promoted a significant recovery of blood flow in CLTI mice 21 days post-ischemia. Besides, they modulated the inflammatory and necrotic related processes, although the CB group presented the slowest ischemic progression along the assay. Moreover, many proteins involved in the repairing mechanisms promoted by cell treatments were identified.</p><p><strong>Conclusions: </strong>The combination of AT-MSCs with AT-ECFCs or with CB-ECFCs promoted similar revascularization in CLTI mice, by restoring blood flow levels, together with the modulation of the inflammatory and necrotic processes, and reduction of muscle damage. The protein changes identified are representative of the molecular mechanisms involved in ECFCs and MSCs-induced revascularization (immune response, vascular repair, muscle regeneration, etc.).</p>","PeriodicalId":15365,"journal":{"name":"Journal of Biomedical Science","volume":"31 1","pages":"71"},"PeriodicalIF":9.0,"publicationDate":"2024-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11247736/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141616575","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":"Enteroviruses: epidemic potential, challenges and opportunities with vaccines.","authors":"Minne Jartti, Malin Flodström-Tullberg, Minna M Hankaniemi","doi":"10.1186/s12929-024-01058-x","DOIUrl":"10.1186/s12929-024-01058-x","url":null,"abstract":"<p><p>Enteroviruses (EVs) are the most prevalent viruses in humans. EVs can cause a range of acute symptoms, from mild common colds to severe systemic infections such as meningitis, myocarditis, and flaccid paralysis. They can also lead to chronic diseases such as cardiomyopathy. Although more than 280 human EV serotypes exist, only four serotypes have licenced vaccines. No antiviral drugs are available to treat EV infections, and global surveillance of EVs has not been effectively coordinated. Therefore, poliovirus still circulates, and there have been alarming epidemics of non-polio enteroviruses. Thus, there is a pressing need for coordinated preparedness efforts against EVs.This review provides a perspective on recent enterovirus outbreaks and global poliovirus eradication efforts with continuous vaccine development initiatives. It also provides insights into the challenges and opportunities in EV vaccine development. Given that traditional whole-virus vaccine technologies are not suitable for many clinically relevant EVs and considering the ongoing risk of enterovirus outbreaks and the potential for new emerging pathogenic strains, the need for new effective and adaptable enterovirus vaccines is emphasized.This review also explores the difficulties in translating promising vaccine candidates for clinical use and summarizes information from published literature and clinical trial databases focusing on existing enterovirus vaccines, ongoing clinical trials, the obstacles faced in vaccine development as well as the emergence of new vaccine technologies. Overall, this review contributes to the understanding of enterovirus vaccines, their role in public health, and their significance as a tool for future preparedness.</p>","PeriodicalId":15365,"journal":{"name":"Journal of Biomedical Science","volume":"31 1","pages":"73"},"PeriodicalIF":9.0,"publicationDate":"2024-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11247760/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141620031","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":"Intracellular domain of epithelial cell adhesion molecule induces Wnt receptor transcription to promote colorectal cancer progression.","authors":"Sushree Shankar Panda, Chi-Chiu Lee, Khamushavalli Geevimaan, Kai-Chi Chen, Shung-Haur Yang, Chia-Ning Shen, Wei-Chun HuangFu, Han-Chung Wu","doi":"10.1186/s12929-024-01057-y","DOIUrl":"10.1186/s12929-024-01057-y","url":null,"abstract":"<p><strong>Background: </strong>Epithelial cell adhesion molecule (EpCAM) has been widely studied as a tumor antigen due to its expression in varieties of solid tumors. Moreover, the glycoprotein contributes to critical cancer-associated cellular functionalities via its extracellular (EpEX) and intracellular (EpICD) domains. In colorectal cancer (CRC), EpCAM has been implicated in the Wnt signaling pathway, as EpICD and β-Catenin are coordinately translocated to the nucleus. Once in the nucleus, EpICD transcriptionally regulates EpCAM target genes that; however, remains unclear whether Wnt signaling is modulated by EpICD activity.</p><p><strong>Methods: </strong>Patient-derived organoids (PDOs), patient-derived xenografts (PDXs), and various CRC cell lines were used to study the roles of EpCAM and EpICD in Wnt receptor expression. Fluorescence and confocal microscopy were used to analyze tumors isolated from PDX and other xenograft models as well as CRC cell lines. EpCAM signaling was intervened with our humanized form of EpCAM neutralizing antibody, hEpAb2-6. Wnt receptor promoters under luciferase reporters were constructed to examine the effects of EpICD. Luciferase reporter assays were performed to evaluate promoter, γ-secretase and Wnt activity. Functional assays including in vivo tumor formation, organoid formation, spheroid and colony formation experiments were performed to study Wnt related phenomena. The therapeutic potential of EpCAM suppression by hEpAb2-6 was evaluated in xenograft and orthotopic models of human CRC.</p><p><strong>Results: </strong>EpICD interacted with the promoters of Wnt receptors (FZD6 and LRP5/6) thus upregulated their transcriptional activity inducing Wnt signaling. Furthermore, activation of Wnt-pathway-associated kinases in the β-Catenin destruction complex (GSK3β and CK1) induced γ-secretase activity to augment EpICD shedding, establishing a positive-feedback loop. Our hEpAb2-6 antibody blocked EpICD-mediated upregulation of Wnt receptor expressions and conferred therapeutic benefits in both PDX and orthotopic models of human CRC.</p><p><strong>Conclusions: </strong>This study uncovers relevant functions of EpCAM where Wnt receptors are upregulated via the transcriptional co-factor activity of EpICD. The resultant enhancement of Wnt signaling induces γ-secretase activity further stimulating EpICD cleavage and its nuclear translocation. Our humanized anti-EpCAM antibody hEpAb2-6 blocks these mechanisms and may thereby provide therapeutic benefit in CRC.</p>","PeriodicalId":15365,"journal":{"name":"Journal of Biomedical Science","volume":"31 1","pages":"72"},"PeriodicalIF":9.0,"publicationDate":"2024-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11247908/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141620032","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":"A glimpse into viral warfare: decoding the intriguing role of highly pathogenic coronavirus proteins in apoptosis regulation.","authors":"Leyi Cheng, Yajuan Rui, Yanpu Wang, Shiqi Chen, Jiaming Su, Xiao-Fang Yu","doi":"10.1186/s12929-024-01062-1","DOIUrl":"10.1186/s12929-024-01062-1","url":null,"abstract":"<p><p>Coronaviruses employ various strategies for survival, among which the activation of endogenous or exogenous apoptosis stands out, with viral proteins playing a pivotal role. Notably, highly pathogenic coronaviruses such as SARS-CoV-2, SARS-CoV, and MERS-CoV exhibit a greater array of non-structural proteins compared to low-pathogenic strains, facilitating their ability to induce apoptosis via multiple pathways. Moreover, these viral proteins are adept at dampening host immune responses, thereby bolstering viral replication and persistence. This review delves into the intricate interplay between highly pathogenic coronaviruses and apoptosis, systematically elucidating the molecular mechanisms underpinning apoptosis induction by viral proteins. Furthermore, it explores the potential therapeutic avenues stemming from apoptosis inhibition as antiviral agents and the utilization of apoptosis-inducing viral proteins as therapeutic modalities. These insights not only shed light on viral pathogenesis but also offer novel perspectives for cancer therapy.</p>","PeriodicalId":15365,"journal":{"name":"Journal of Biomedical Science","volume":"31 1","pages":"70"},"PeriodicalIF":9.0,"publicationDate":"2024-07-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11245872/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141603699","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":"Exosomes: a review of biologic function, diagnostic and targeted therapy applications, and clinical trials","authors":"Yi-Fan Chen, Frank Luh, Yuan-Soon Ho, Yun Yen","doi":"10.1186/s12929-024-01055-0","DOIUrl":"https://doi.org/10.1186/s12929-024-01055-0","url":null,"abstract":"Exosomes are extracellular vesicles generated by all cells and they carry nucleic acids, proteins, lipids, and metabolites. They mediate the exchange of substances between cells,thereby affecting biological properties and activities of recipient cells. In this review, we briefly discuss the composition of exocomes and exosome isolation. We also review the clinical applications of exosomes in cancer biology as well as strategies in exosome-mediated targeted drug delivery systems. Finally, the application of exosomes in the context of cancer therapeutics both in practice and literature are discussed.","PeriodicalId":15365,"journal":{"name":"Journal of Biomedical Science","volume":"18 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2024-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141588244","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":"Dual inhibition of SUMOylation and MEK conquers MYC-expressing KRAS-mutant cancers by accumulating DNA damage","authors":"Hiroshi Kotani, Hiroko Oshima, Justin C. Boucher, Tomoyoshi Yamano, Hiroyuki Sakaguchi, Shigeki Sato, Koji Fukuda, Akihiro Nishiyama, Kaname Yamashita, Koushiro Ohtsubo, Shinji Takeuchi, Takumi Nishiuchi, Masanobu Oshima, Marco L. Davila, Seiji Yano","doi":"10.1186/s12929-024-01060-3","DOIUrl":"https://doi.org/10.1186/s12929-024-01060-3","url":null,"abstract":"KRAS mutations frequently occur in cancers, particularly pancreatic ductal adenocarcinoma, colorectal cancer, and non-small cell lung cancer. Although KRASG12C inhibitors have recently been approved, effective precision therapies have not yet been established for all KRAS-mutant cancers. Many treatments for KRAS-mutant cancers, including epigenome-targeted drugs, are currently under investigation. Small ubiquitin-like modifier (SUMO) proteins are a family of small proteins covalently attached to and detached from other proteins in cells via the processes called SUMOylation and de-SUMOylation. We assessed whether SUMOylation inhibition was effective in KRAS-mutant cancer cells. The efficacy of the first-in-class SUMO-activating enzyme E inhibitor TAK-981 (subasumstat) was assessed in multiple human and mouse KRAS-mutated cancer cell lines. A gene expression assay using a TaqMan array was used to identify biomarkers of TAK-981 efficacy. The biological roles of SUMOylation inhibition and subsequent regulatory mechanisms were investigated using immunoblot analysis, immunofluorescence assays, and mouse models. We discovered that TAK-981 downregulated the expression of the currently undruggable MYC and effectively suppressed the growth of MYC-expressing KRAS-mutant cancers across different tissue types. Moreover, TAK-981-resistant cells were sensitized to SUMOylation inhibition via MYC-overexpression. TAK-981 induced proteasomal degradation of MYC by altering the balance between SUMOylation and ubiquitination and promoting the binding of MYC and Fbxw7, a key factor in the ubiquitin–proteasome system. The efficacy of TAK-981 monotherapy in immunocompetent and immunodeficient mouse models using a mouse-derived CMT167 cell line was significant but modest. Since MAPK inhibition of the KRAS downstream pathway is crucial in KRAS-mutant cancer, we expected that co-inhibition of SUMOylation and MEK might be a good option. Surprisingly, combination treatment with TAK-981 and trametinib dramatically induced apoptosis in multiple cell lines and gene-engineered mouse-derived organoids. Moreover, combination therapy resulted in long-term tumor regression in mouse models using cell lines of different tissue types. Finally, we revealed that combination therapy complementally inhibited Rad51 and BRCA1 and accumulated DNA damage. We found that MYC downregulation occurred via SUMOylation inhibition in KRAS-mutant cancer cells. Our findings indicate that dual inhibition of SUMOylation and MEK may be a promising treatment for MYC-expressing KRAS-mutant cancers by enhancing DNA damage accumulation.","PeriodicalId":15365,"journal":{"name":"Journal of Biomedical Science","volume":"5 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2024-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141588243","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}