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Cancer represents a major global public health burden, with new cases estimated to increase from 14 million in 2012 to 24 million by 2035. Primary prevention is an effective strategy to reduce the costs associated with cancer burden. For example, measures to ban tobacco consumption have dramatically decreased lung cancer incidence and vaccination against human papillomavirus can prevent cervical cancer development. Unfortunately, the etiological factors of many cancer types are not completely clear or are difficult to actively control; therefore, the primary prevention of such cancers is not practical. In this review, we update the progress on precision therapy by targeting the whole carcinogenesis process, especially for three high-risk groups: (1) those with chronic inflammation, (2) those with inherited germline mutations, and (3) those with precancerous lesions like polyps, gastritis, actinic keratosis or dysplasia. We believe that attenuating chronic inflammation, treating precancerous lesions, and removing high-risk tissues harboring germline mutations are precision methods for cancer prevention.
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Ubiquitination, a pivotal posttranslational modification of proteins, plays a fundamental role in regulating protein stability. The dysregulation of ubiquitinating and deubiquitinating enzymes is a common feature in various cancers, underscoring the imperative to investigate ubiquitin ligases and deubiquitinases (DUBs) for insights into oncogenic processes and the development of therapeutic interventions. In this review, we discuss the contributions of the ubiquitin-proteasome system (UPS) in all hallmarks of cancer and progress in drug discovery. We delve into the multiple functions of the UPS in oncology, including its regulation of multiple cancer-associated pathways, its role in metabolic reprogramming, its engagement with tumor immune responses, its function in phenotypic plasticity and polymorphic microbiomes, and other essential cellular functions. Furthermore, we provide a comprehensive overview of novel anticancer strategies that leverage the UPS, including the development and application of proteolysis targeting chimeras (PROTACs) and molecular glues.
Assuntos
Enzimas Desubiquitinantes , Neoplasias , Complexo de Endopeptidases do Proteassoma , Ubiquitinação , Humanos , Neoplasias/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Animais , Complexo de Endopeptidases do Proteassoma/metabolismo , Enzimas Desubiquitinantes/metabolismo , Proteólise , Ubiquitina/metabolismo , Antineoplásicos/uso terapêutico , Antineoplásicos/farmacologia , Processamento de Proteína Pós-Traducional , Terapia de Alvo Molecular , Ubiquitina-Proteína Ligases/metabolismoRESUMO
Hepatocyte growth factor receptor (c-Met) is a suitable molecular target for the targeted therapy of cancer. Novel c-Met-targeting drugs need to be developed because conventional small-molecule inhibitors and antibodies of c-Met have some limitations. To synthesize such drugs, we developed a bispecific DNA nanoconnector (STPA) to inhibit c-Met function. STPA was constructed by using DNA triangular prism as a scaffold and aptamers as binding molecules. After c-Met-specific SL1 and nucleolin-specific AS1411 aptamers were integrated with STPA, STPA could bind to c-Met and nucleolin on the cell membrane. This led to the formation of the c-Met/STPA/nucleolin complex, which in turn blocked c-Met activation. In vitro experiments showed that STPA could not only inhibit the c-Met signaling pathways but also facilitate c-Met degradation through lysosomes. STPA also inhibited c-Met-promoted cell migration, invasion, and proliferation. The results of in vivo experiments showed that STPA could specifically target to tumor site in xenograft mouse model, and inhibit tumor growth with low toxicity by downregulating c-Met pathways. This study provided a novel and simple strategy to develop c-Met-targeting drugs for the targeted therapy of cancer.
Assuntos
Aptâmeros de Nucleotídeos , Proliferação de Células , Neoplasias , Proteínas Proto-Oncogênicas c-met , Transdução de Sinais , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-met/metabolismo , Humanos , Animais , Transdução de Sinais/efeitos dos fármacos , Camundongos , Proliferação de Células/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Neoplasias/patologia , Linhagem Celular Tumoral , Aptâmeros de Nucleotídeos/farmacologia , Aptâmeros de Nucleotídeos/química , Nucleolina , Movimento Celular/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto , Proteínas de Ligação a RNA/metabolismo , Fosfoproteínas/metabolismo , Terapia de Alvo Molecular , DNA/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/química , OligodesoxirribonucleotídeosRESUMO
Serine/threonine protein kinase 19 (STK19) has been reported to phosphorylate and activate oncogenic NRAS to promote melanomagenesis. However, concerns have been raised about whether STK19 is a kinase. STK19 has also been identified as a putative factor involved in the transcription-coupled nucleotide excision repair (TC-NER) pathway. In this study, we determined the 1.32 Å crystal structure of human STK19. The structure reveals that STK19 is a winged helix (WH) protein consisting of three tandem WH domains. STK19 binds more strongly to double-stranded DNA and RNA (dsDNA/dsRNA) than to ssDNA. A positively charged patch centered on helix WH3-H1 contributes to dsDNA binding, which is unusual because the WH domain typically uses helix H3 as the recognition helix. Importantly, mutations of the conserved residues in the basic patch, K186N, R200W, and R215W, are found in cancer patients, and these mutations compromise STK19 DNA binding. Other mutations have been predicted to produce a similar effect, including two mutations that disrupt the nuclear localization signal (NLS) motif. These mutations may indirectly impact the DNA binding capacity of STK19 by interfering with its nuclear localization.
Assuntos
DNA , Mutação , Ligação Proteica , Proteínas Serina-Treonina Quinases , Humanos , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/química , DNA/metabolismo , Neoplasias/genética , Neoplasias/metabolismo , Modelos Moleculares , Cristalografia por Raios X , Sequência de AminoácidosRESUMO
JAK2/STAT3/MYC axis is dysregulated in nearly 70 % of human cancers, but targeting this pathway therapeutically remains a big challenge in cancer therapy. In this study, genes associated with JAK2, STAT3, and MYC were analyzed, and potential target genes were selected. Leucine-rich PPR motif-containing protein (LRPPRC) whose function and regulation are not fully understood, emerged as one of top 3 genes in terms of RNA epigenetic modification. Here, we demonstrate LRPPRC may be an independent prognostic indicator besides JAK2, STAT3, and MYC. Mechanistically, LRPPRC impairs N6-methyladenosine (m6A) modification of JAK2, STAT3, and MYC to facilitate nuclear mRNA export and expression. Meanwhile, excess LRPPRC act as a scaffold protein binding to JAK2 and STAT3 to enhance stability of JAK2-STAT3 complex, thereby facilitating JAK2/STAT3/MYC axis activation to promote esophageal squamous cell carcinoma (ESCC) progression. Furthermore, 5,7,4'-trimethoxyflavone was verified to bind to LRPPRC, STAT3, and CDK1, dissociating LRPPRC-JAK2-STAT3 and JAK2-STAT3-CDK1 interaction, leading to impaired tumorigenesis in 4-Nitroquinoline N-oxide induced ESCC mouse models and suppressed tumor growth in ESCC patient derived xenograft mouse models. In summary, this study suggests regulation of m6A modification by LRPPRC, and identifies a novel triplex target compound, suggesting that targeting LRPPRC-mediated JAK2/STAT3/MYC axis may overcome JAK2/STAT3/MYC dependent tumor therapeutic dilemma.
Assuntos
Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Janus Quinase 2 , Fator de Transcrição STAT3 , Humanos , Carcinoma de Células Escamosas do Esôfago/tratamento farmacológico , Carcinoma de Células Escamosas do Esôfago/metabolismo , Carcinoma de Células Escamosas do Esôfago/patologia , Carcinoma de Células Escamosas do Esôfago/genética , Fator de Transcrição STAT3/metabolismo , Animais , Janus Quinase 2/metabolismo , Camundongos , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/patologia , Neoplasias Esofágicas/genética , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Progressão da Doença , Adenosina/análogos & derivados , Adenosina/farmacologia , Adenosina/metabolismo , Adenosina/química , Flavonas/farmacologia , Flavonas/química , Proteína Quinase CDC2/metabolismo , Proteína Quinase CDC2/genética , Transdução de Sinais/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-myc/metabolismo , Proteínas Proto-Oncogênicas c-myc/genética , Feminino , Masculino , Flavonoides/farmacologia , Flavonoides/química , Ensaios Antitumorais Modelo de Xenoenxerto , Proteínas de Neoplasias/metabolismo , Proteínas de Neoplasias/genéticaRESUMO
Novel strategies in intratumoral injection and emerging immunotherapies have heralded a new era of precise cancer treatments. The affinity of SARS-CoV-2 to ACE2 receptors, a feature which facilitates virulent human infection, is leveraged in this research. Colon cancer cells, with their high ACE2 expression, provide a potentially strategic target for using this SARS-CoV-2 feature. While the highly expression of ACE2 is observed in several cancer types, the idea of using the viral spike protein for targeting colon cancer cells offers a novel approach in cancer treatment. Intratumoral delivery of nucleic acid-based drugs is a promising alternative to overcoming the limitations of existing therapies. The increasing importance of nucleic acids in this realm, and the use of Lipid Nanoparticles (LNPs) for local delivery of nucleic acid therapeutics, are important breakthroughs. LNPs protect nucleic acid drugs from degradation and enhance cellular uptake, making them a rapidly evolving nano delivery system with high precision and adaptability. Our study leveraged a tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) combined with a receptor-binding domain from the SARS-CoV-2 spike protein, encapsulated in LNPs, to target colon cancer cells. Our results indicated that the TRAIL fusion-mRNA induced apoptosis in vitro and in vivo. Collectively, our findings highlight LNP-encapsulated TRAIL fusion-mRNA as a potential colon cancer therapy.
Assuntos
Apoptose , Neoplasias do Colo , Lipossomos , Nanopartículas , RNA Mensageiro , Ligante Indutor de Apoptose Relacionado a TNF , Humanos , Apoptose/efeitos dos fármacos , Neoplasias do Colo/terapia , Neoplasias do Colo/genética , Neoplasias do Colo/patologia , Neoplasias do Colo/tratamento farmacológico , Animais , Ligante Indutor de Apoptose Relacionado a TNF/genética , Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/metabolismo , Camundongos , Linhagem Celular Tumoral , SARS-CoV-2 , Camundongos Nus , Enzima de Conversão de Angiotensina 2/metabolismo , Enzima de Conversão de Angiotensina 2/genéticaRESUMO
Esophageal squamous cell carcinoma (ESCC) is the predominant form of esophageal cancer and is characterized by an unfavorable prognosis. To elucidate the distinct molecular alterations in ESCC and investigate therapeutic targets, we performed a comprehensive analysis of transcriptomics, proteomics, and phosphoproteomics data derived from 60 paired treatment-naive ESCC and adjacent nontumor tissue samples. Additionally, we conducted a correlation analysis to describe the regulatory relationship between transcriptomic and proteomic processes, revealing alterations in key metabolic pathways. Unsupervised clustering analysis of the proteomics data stratified patients with ESCC into 3 subtypes with different molecular characteristics and clinical outcomes. Notably, subtype III exhibited the worst prognosis and enrichment in proteins associated with malignant processes, including glycolysis and DNA repair pathways. Furthermore, translocase of inner mitochondrial membrane domain containing 1 (TIMMDC1) was validated as a potential prognostic molecule for ESCC. Moreover, integrated kinase-substrate network analysis using the phosphoproteome nominated candidate kinases as potential targets. In vitro and in vivo experiments further confirmed casein kinase II subunit α (CSNK2A1) as a potential kinase target for ESCC. These underlying data represent a valuable resource for researchers that may provide better insights into the biology and treatment of ESCC.
Assuntos
Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Proteômica , Humanos , Carcinoma de Células Escamosas do Esôfago/genética , Carcinoma de Células Escamosas do Esôfago/metabolismo , Carcinoma de Células Escamosas do Esôfago/patologia , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/patologia , Proteômica/métodos , Masculino , Camundongos , Prognóstico , Feminino , Animais , Regulação Neoplásica da Expressão Gênica , Linhagem Celular Tumoral , Pessoa de Meia-Idade , Caseína Quinase II/metabolismo , Caseína Quinase II/genética , Transcriptoma , Biomarcadores Tumorais/metabolismo , Biomarcadores Tumorais/genética , MultiômicaRESUMO
BACKGROUND: Colorectal cancer (CRC) continues to be a major global health challenge, ranking as a top cause of cancer-related mortality. Alarmingly, the five-year survival rate for CRC patients hovers around a mere 10-30 %. The disruption of fibroblast growth factor receptor (FGFRs) signaling pathways is significantly implicated in the onset and advancement of CRC, presenting a promising target for therapeutic intervention in CRC management. Further investigation is essential to comprehensively elucidate FGFR1's function in CRC and to create potent therapies that specifically target FGFR1. PURPOSE: This study aims to demonstrate the oncogenic role of FGFR1 in colorectal cancer and to explore the potential of ß,ß-dimethylacrylalkannin (ß,ß-DMAA) as a therapeutic option to inhibit FGFR1. METHODS: In this research, we employed a comprehensive suite of techniques including tissue array, kinase profiling, computational docking, knockdown assay to predict and explore the inhibitor of FGFR1. Furthermore, we utilized kinase assay, pull-down, cell proliferation tests, and Patient derived xenograft (PDX) mouse models to further investigate a novel FGFR1 inhibitor and its impact on the growth of CRC. RESULTS: In our research, we discovered that FGFR1 protein is markedly upregulated in colorectal cancer tissues, suggesting a significant role in regulating cellular proliferation, particularly in patients with colorectal cancer. Furthermore, we conducted a computational docking, kinase profiling analysis, simulation and identified that ß,ß-DMAA could directly bind with FGFR1 within ATP binding pocket domain. Cell-based assays confirmed that ß,ß-DMAA effectively inhibited the proliferation of colon cancer cells and also triggered cell cycle arrest, apoptosis, and altered FGFR1-mediated signaling pathways. Moreover, ß,ß-DMAA effectively attenuated the development of PDX tumors in mice that were FGFR1-positive, with no notable toxicity observed. In summary, our study highlights the pivotal role of FGFR1 in colorectal cancer, suggesting that inhibiting FGFR1 activity could be a promising strategy for therapeutic intervention. We present strong evidence that targeting FGFR1 with ß,ß-DMAA is a viable approach for the management of colorectal cancer. Given its low toxicity and high efficacy, ß,ß-DMAA, as an FGFR1 inhibitor, warrants further investigation in clinical settings for the treatment of FGFR1-positive tumors.
Assuntos
Proliferação de Células , Neoplasias Colorretais , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos , Animais , Feminino , Humanos , Camundongos , Acrilamidas/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Neoplasias Colorretais/tratamento farmacológico , Simulação de Acoplamento Molecular , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/metabolismo , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is one of the leading causes of digestive system tumor related death in the world. Unfortunately, effective chemopreventive agent is lack for patients with ESCC in clinical practice, which leads to the extremely high mortality rate. METHODS: A library of prescribed drugs was screened for finding critical anti-tumor properties in ESCC cells. The phosphoproteomics, kinase array, pulldown assay and drug affinity responsive target stabilization assay (DARTS) were applied to explore mechanisms and searched for synergistic targets. Established models of PDX in mice were used to determine the therapeutic effect of domperidone. RESULTS: After screening a library of prescribed drugs, we discovered that domperidone has anti-tumor properties. Domperidone, acting as a gastroprokinetic agent, has been widely used in clinic for gastrointestinal motility disorders. Despite limited research, there are indications that domperidone may have anti-tumor properties. In this study, we determined that domperidone significantly inhibited ESCC proliferation in vitro and in vivo. We employed phosphoproteomics to reveal p-ERK, and p-SMAD3 down-regulation upon domperidone treatment. Then, the results of kinase assay and pulldown assay further validated that domperidone directly combined with MEK1/2 and CDK4, leading to the inhibition of their kinase activity. Furthermore, our results revealed that MEK/ERK and CDK4/SMAD3 signal pathway were major pathways in domperidone against ESCC. CONCLUSION: Collectively, these findings suggest that domperidone serves as an effective "multi-target" inhibitor of MEK1/2 and CDK4, offering potential benefits for the chemoprevention of ESCC.
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Protein translation is a tightly regulated cellular process that is essential for gene expression and protein synthesis. The deregulation of this process is increasingly recognized as a critical factor in the pathogenesis of various human diseases. In this review, we discuss how deregulated translation can lead to aberrant protein synthesis, altered cellular functions, and disease progression. We explore the key mechanisms contributing to the deregulation of protein translation, including functional alterations in translation factors, tRNA, mRNA, and ribosome function. Deregulated translation leads to abnormal protein expression, disrupted cellular signaling, and perturbed cellular functions- all of which contribute to disease pathogenesis. The development of ribosome profiling techniques along with mass spectrometry-based proteomics, mRNA sequencing and single-cell approaches have opened new avenues for detecting diseases related to translation errors. Importantly, we highlight recent advances in therapies targeting translation-related disorders and their potential applications in neurodegenerative diseases, cancer, infectious diseases, and cardiovascular diseases. Moreover, the growing interest lies in targeted therapies aimed at restoring precise control over translation in diseased cells is discussed. In conclusion, this comprehensive review underscores the critical role of protein translation in disease and its potential as a therapeutic target. Advancements in understanding the molecular mechanisms of protein translation deregulation, coupled with the development of targeted therapies, offer promising avenues for improving disease outcomes in various human diseases. Additionally, it will unlock doors to the possibility of precision medicine by offering personalized therapies and a deeper understanding of the molecular underpinnings of diseases in the future.
Assuntos
Fenômenos Biológicos , Neoplasias , Humanos , Ribossomos/genética , Neoplasias/terapia , Neoplasias/tratamento farmacológico , RNA Mensageiro/genética , Biossíntese de Proteínas/genéticaRESUMO
The worldwide incidence and mortality rates of esophageal squamous cell carcinoma (ESCC) have increased over the last decade. Moreover, molecular targets that may benefit the therapeutics of patients with ESCC have not been fully characterized. Our study discovered that thousand and one amino-acid protein kinase 1 (TAOK1) is highly expressed in ESCC tumor tissues and cell lines. Knock-down of TAOK1 suppresses ESCC cell proliferation in vitro and patient-derived xenograft or cell-derived xenograft tumors growth in vivo. Moreover, TAOK1 overexpression promotes ESCC growth in vitro and in vivo. Additionally, we identified that the natural small molecular compound resveratrol binds to TAOK1 directly and diminishes the kinase activity of TAOK1. Targeting TAOK1 directly with resveratrol significantly inhibits cell proliferation, induces cell cycle arrest and apoptosis, and suppresses tumor growth in ESCC. Furthermore, the silencing of TAOK1 or the application of resveratrol attenuated the activation of TAOK1 downstream signaling effectors. Interestingly, combining resveratrol with paclitaxel, cisplatin, or 5-fluorouracil synergistically enhanced their therapeutic effects against ESCC. In conclusion, this work illustrates the underlying oncogenic function of TAOK1 and provides a theoretical basis for the application of targeting TAOK1 therapy to the clinical treatment of ESCC.
Assuntos
Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Proteínas Serina-Treonina Quinases , Humanos , Apoptose , Linhagem Celular Tumoral , Proliferação de Células , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/metabolismo , Carcinoma de Células Escamosas do Esôfago/tratamento farmacológico , Carcinoma de Células Escamosas do Esôfago/genética , Carcinoma de Células Escamosas do Esôfago/metabolismo , Regulação Neoplásica da Expressão Gênica , Proteínas Serina-Treonina Quinases/efeitos dos fármacos , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Resveratrol/farmacologia , Resveratrol/uso terapêuticoRESUMO
OBJECTIVE: Nonalcoholic fatty liver disease (NAFLD) is an emerging public health threat as the most common chronic liver disease worldwide. However, there remains no effective medication to improve NAFLD. G protein-coupled receptors (GPCRs) are the most frequently investigated drug targets family. The Regulator of G protein signaling 14 (RGS14), as an essential negative modulator of GPCR signaling, plays important regulatory roles in liver damage and inflammatory responses. However, the role of RGS14 in NAFLD remains largely unclear. METHODS AND RESULTS: In this study, we found that RGS14 was decreased in hepatocytes in NAFLD individuals in a public database. We employed genetic engineering technique to explore the function of RGS14 in NAFLD. We demonstrated that RGS14 overexpression ameliorated lipid accumulation, inflammatory response and liver fibrosis in hepatocytes in vivo and in vitro. Whereas, hepatocyte specific Rgs14-knockout (Rgs14-HKO) exacerbated high fat high cholesterol diet (HFHC) induced NASH. Further molecular experiments demonstrated that RGS14 depended on GDI activity to attenuate HFHC-feeding NASH. More importantly, RGS14 interacted with Guanine nucleotide-binding protein (Gi) alpha 1 and 3 (Giα1/3, gene named GNAI1/3), promoting the generation of cAMP and then activating the subsequent AMPK pathways. GNAI1/3 knockdown abolished the protective role of RGS14, indicating that RGS14 binding to Giα1/3 was required for prevention against hepatic steatosis. CONCLUSIONS: RGS14 plays a protective role in the progression of NAFLD. RGS14-Giα1/3 interaction accelerated the production of cAMP and then activated cAMP-AMPK signaling. Targeting RGS14 or modulating the RGS14-Giα1/3 interaction may be a potential strategy for the treatment of NAFLD in the future.
Assuntos
Hepatopatia Gordurosa não Alcoólica , Proteínas RGS , Transdução de Sinais , Humanos , Proteínas Quinases Ativadas por AMP/metabolismo , Hepatócitos/metabolismo , Hepatopatia Gordurosa não Alcoólica/metabolismo , Proteínas RGS/metabolismoRESUMO
Tumor cell-targeting molecules play a vital role in cancer diagnosis, targeted therapy, and biomarker discovery. Aptamers are emerging as novel targeting molecules with unique advantages in cancer research. In this work, we have developed several DNA aptamers through cell-based systematic evolution of ligands by exponential enrichment (Cell-SELEX). The selected SYL-6 aptamer can bind to a variety of cancer cells with high signal. Tumor tissue imaging demonstrated that SYL-6-Cy5 fluorescent probe was able to recognize multiple clinical tumor tissues but not the normal tissues, which indicates great potential of SYL-6 for clinical tumor diagnosis. Meanwhile, we identified prohibitin 2 (PHB2) as the molecular target of SYL-6 using mass spectrometry, pull-down and RNA interference assays. Moreover, SYL-6 can be used as a delivery vehicle to carry with doxorubicin (Dox) chemotherapeutic agents for antitumor targeted chemotherapy. The constructed SYL-6-Dox can not only selectively kill tumor cells in vitro, but also inhibit tumor growth with reduced side effects in vivo. This work may provide a general tumor cell-targeting molecule and a potential biomarker for cancer diagnosis and targeted therapy.
Assuntos
Aptâmeros de Nucleotídeos , Neoplasias , Humanos , Aptâmeros de Nucleotídeos/metabolismo , Proibitinas , Doxorrubicina/farmacologia , Neoplasias/tratamento farmacológico , Biomarcadores , Técnica de Seleção de Aptâmeros/métodos , Linhagem Celular TumoralRESUMO
Receptor tyrosine kinase (RTK) plays a crucial role in cancer progression, and it has been identified as a key drug target for cancer targeted therapy. Although traditional RTK-targeting drugs are effective, there are some limitations that potentially hinder the further development of RTK-targeting drugs. Therefore, it is urgently needed to develop novel, simple, and general RTK-targeting inhibitors with a new mechanism of action for cancer targeted therapy. Here, a cell membrane-anchored RTK-targeting DNA nanoinhibitor is developed to inhibit RTK function. By using a DNA tetrahedron as a framework, RTK-specific aptamers as the recognition elements, and cholesterol as anchoring molecules, this DNA nanoinhibitor could rapidly anchor on the cell membrane and specifically bind to RTK. Compared with traditional RTK-targeting inhibitors, this DNA nanoinhibitor does not need to bind at a limited domain on RTK, which increases the possibilities of developing RTK inhibitors. With the cellular-mesenchymal to epithelial transition factor (c-Met) as a target RTK, the DNA nanoinhibitor can not only induce steric hindrance effects to inhibit c-Met activation but also reduce the c-Met level via lysosome-mediated protein degradation and thus inhibition of c-Met signaling pathways and related cell behaviors. Moreover, the DNA nanoinhibitor is feasible for other RTKs by just replacing aptamers. This work may provide a novel, simple, and general RTK-targeting nanoinhibitor and possess great value in RTK-targeted cancer therapy.
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Signal transducer and activator of transcription 3 (STAT3) is a transcriptional factor involved in almost all cancer hallmark features including tumor proliferation, metastasis, angiogenesis, immunosuppression, tumor inflammation, metabolism reprogramming, drug resistance, cancer stemness. Therefore, STAT3 has become a promising therapeutic target in a wide range of cancers. This review focuses on the up-to-date knowledge of STAT3 signaling in cancer. We summarize both the positive and negative modulators of STAT3 together with the cancer hallmarks involving activities regulated by STAT3 and highlight its extremely sophisticated regulation on immunosuppression in tumor microenvironment and metabolic reprogramming. Direct and indirect inhibitors of STAT3 in preclinical and clinical studies also have been summarized and discussed. Additionally, we highlight and propose new strategies of targeting STAT3 and STAT3-based combinations with established chemotherapy, targeted therapy, immunotherapy and combination therapy. These efforts may provide new perspectives for STAT3-based target therapy in cancer.
Assuntos
Neoplasias , Fator de Transcrição STAT3 , Humanos , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/genética , Neoplasias/patologia , Transdução de Sinais , Terapia de Imunossupressão , Descoberta de Drogas , Microambiente TumoralRESUMO
BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is an aggressive and deadly malignancy characterized by late-stage diagnosis, therapy resistance, and a poor 5-year survival rate. Finding novel therapeutic targets and their inhibitors for ESCC prevention and therapy is urgently needed. METHODS: We investigated the proviral integration site for maloney murine leukemia virus 3 (Pim-3) protein levels using immunohistochemistry. Using Methyl Thiazolyl Tetrazolium and clone formation assay, we verified the function of Pim-3 in cell proliferation. The binding and inhibition of Pim-3 by corynoline were verified by computer docking, pull-down assay, cellular thermal shift assay, and kinase assay. Cell proliferation, Western blot, and a patient-derived xenograft tumor model were performed to elucidate the mechanism of corynoline inhibiting ESCC growth. RESULTS: Pim-3 was highly expressed in ESCC and played an oncogenic role. The augmentation of Pim-3 enhanced cell proliferation and tumor development by phosphorylating mitogen-activated protein kinase 1 (MAPK1) at T185 and Y187. The deletion of Pim-3 induced apoptosis with upregulated cleaved caspase-9 and lower Bcl2 associated agonist of cell death (BAD) phosphorylation at S112. Additionally, binding assays demonstrated corynoline directly bound with Pim-3, inhibiting its activity, and suppressing ESCC growth. CONCLUSIONS: Our findings suggest that Pim-3 promotes ESCC progression. Corynoline inhibits ESCC progression through targeting Pim-3.
Assuntos
Alcaloides de Berberina , Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Animais , Camundongos , Humanos , Carcinoma de Células Escamosas do Esôfago/tratamento farmacológico , Carcinoma de Células Escamosas do Esôfago/patologia , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Movimento Celular , ApoptoseRESUMO
Patients with colorectal cancer (CRC) suffer from poor prognosis and lack effective drugs. Dihydroartemisinin (DHA) has anti-cancer potential but the mechanism remains unclear. We elucidated the effects and mechanism of DHA on CRC development with the aim of providing an effective, low-toxicity drug and a novel strategy for CRC. Herein, proliferation assay, transwell assay, tube formation assay, metastasis models, PDX model and AOM/DSS model were used to reveal the effects of DHA on CRC. The key pathway and target were identified by RNA-seq, ChIP, molecular docking, pull down and dual-luciferase reporter assays. As a result, DHA showed a strong inhibitory effect on the growth, metastasis and angiogenesis of CRC with no obvious toxicity, and the inhibitory effect was similar to that of the clinical drug Capecitabine (Cap). Indeed, DHA directly targeted GSK-3ß to inhibit CRC development through the GSK-3ß/TCF7/MMP9 pathway. Meaningfully, DHA in combination with Cap enhanced the anti-cancer effect, and alleviated Cap-induced diarrhoea, immunosuppression and inflammation. In conclusion, DHA has the potential to be an effective and low-toxicity drug for the treatment of CRC. Furthermore, DHA in combination with Cap could be a novel therapeutic strategy for CRC with improved efficacy and reduced side effects.
Assuntos
Artemisininas , Neoplasias Colorretais , Humanos , Capecitabina/farmacologia , Capecitabina/uso terapêutico , Glicogênio Sintase Quinase 3 beta , Neoplasias Colorretais/patologia , Metaloproteinase 9 da Matriz , Simulação de Acoplamento Molecular , Linhagem Celular Tumoral , Proliferação de Células , Fator 1 de Transcrição de Linfócitos TRESUMO
The RAS/mitogen-activated protein kinase (MAPK) signaling cascade is commonly dysregulated in human malignancies by processes driven by RAS or RAF oncogenes. Among the members of the RAF kinase family, CRAF plays an important role in the RAS-MAPK signaling pathway, as well as in the progression of cancer. Recent research has provided evidence implicating the role of CRAF in the physiological regulation and the resistance to BRAF inhibitors through MAPK-dependent and MAPK-independent mechanisms. Nevertheless, the effectiveness of solely targeting CRAF kinase activity remains controversial. Moreover, the kinase-independent function of CRAF may be essential for lung cancers with KRAS mutations. It is imperative to develop strategies to enhance efficacy and minimize toxicity in tumors driven by RAS or RAF oncogenes. The review investigates CRAF alterations observed in cancers and unravels the distinct roles of CRAF in cancers propelled by diverse oncogenes. This review also seeks to summarize CRAF-interacting proteins and delineate CRAF's regulation across various cancer hallmarks. Additionally, we discuss recent advances in pan-RAF inhibitors and their combination with other therapeutic approaches to improve treatment outcomes and minimize adverse effects in patients with RAF/RAS-mutant tumors. By providing a comprehensive understanding of the multifaceted role of CRAF in cancers and highlighting the latest developments in RAF inhibitor therapies, we endeavor to identify synergistic targets and elucidate resistance pathways, setting the stage for more robust and safer combination strategies for cancer treatment.
Assuntos
Sistema de Sinalização das MAP Quinases , Proteínas Proto-Oncogênicas B-raf , Humanos , Linhagem Celular Tumoral , Transdução de Sinais , Fosforilação , Mutação , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas c-raf/genética , Proteínas Proto-Oncogênicas c-raf/metabolismoRESUMO
Esophageal squamous cell carcinoma (ESCC) is a prevalent malignant tumor of the digestive tract with a low 5-year survival rate due to the lack of effective treatment methods. Although therapeutic monoclonal antibodies (mAbs) now play an important role in cancer therapy, effective targeted mAbs are still lacking for ESCC. B7-H3 is highly expressed in a variety of tumors and has emerged as a promising therapeutic target. Several mAbs against B7-H3 have advanced to clinical trials, but their development has not yet been pursued for ESCC. Here, we developed a humanized and Fc-engineered anti-B7H3 mAb 24F-Hu-mut2 and systematically evaluated its anti-tumor activity in vitro and in vivo. The 24F-Hu-mut2 was humanized and modified in Fc fragment to obtain stronger antibody-dependent cell-mediated cytotoxicity(ADCC) activity and nanomolar affinity. Furthermore, both of ESCC cell-derived xenograft (CDX) and patient-derived xenograft (PDX) mice models indicated that 24F-Hu-mut2 displayed potent in vivo anti-tumor activity. In addition, a computational docking model showed that the mAb bound to IgC1 and IgC2 domain of B7-H3, which is closer to the cell membrane. Consistently, our ELISA results verified the binding of 24F-Hu-WT and IgC1 and IgC2. Our results indicate that 24F-Hu-mut2 has significant anti-ESCC activity both in vitro and in vivo, and this monoclonal antibody may be a promising antibody against ESCC and other B7-H3 overexpressing tumors.
Assuntos
Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Humanos , Animais , Camundongos , Carcinoma de Células Escamosas do Esôfago/tratamento farmacológico , Neoplasias Esofágicas/tratamento farmacológico , Anticorpos Monoclonais Humanizados/farmacologia , Anticorpos Monoclonais/farmacologia , Citotoxicidade Celular Dependente de AnticorposRESUMO
BACKGROUND: Although sulforaphene has potential anticancer effects, little is known about its effect on oesophageal squamous cell carcinoma (ESCC) invasiveness. METHODS: To investigate whether sulforaphene inhibits the growth of oesophageal cancer cells, MTT and anchorage-independent cell growth assays were performed. Global changes in the proteome and phosphoproteome of oesophageal cancer cells after sulforaphene treatment were analysed by mass spectrometry (MS), and the underlying molecular mechanism was further verified by in vivo and in vitro experiments. RESULTS: Sulforaphene treatment markedly affected proteins that regulate several cellular processes in oesophageal cancer cells, and mitogen- and stress-activated kinase 2 (MSK2) was the main genetic target of sulforaphene in reducing the growth of oesophageal cancer cells. Sulforaphene significantly suppressed ESCC cell proliferation in vitro and reduced the tumour size in an oesophageal patient-derived xenograft (PDX) SCID mouse model. Furthermore, the binding of sulforaphane to MSK2 in vitro was verified using a cellular thermal dhift assay, and the effect of MSK2 knockdown on the ESCC phenotype was observed using a shMSK2 model. CONCLUSION: The results showed that sulforaphene suppresses ESCC growth in both human oesophageal squamous cells and PDX mouse model by inhibiting MSK2 expression, implicating sulforaphene as a promising candidate for ESCC treatment.