RESUMO
Gastrointestinal cancers (GICs) are highly prevalent cancers that threaten human health worldwide. The Wnt/ß-catenin signaling pathway has been reported to play a pivotal role in the carcinogenesis of GICs. Numerous interventions targeting the Wnt/ß-catenin signaling in GICs are currently being tested in clinical trials with promising results. Unfortunately, there are no clinically approved drugs that effectively target this pathway. This comprehensive review aims to evaluate the impact of clinical therapies targeting the Wnt/ß-catenin signaling pathway in GICs. By integrating data from bioinformatics databases and recent literature from the past five years, we examine the heterogeneous expression and regulatory mechanisms of Wnt/ß-catenin pathway genes and proteins in GICs. Specifically, we focus on expression patterns, mutation frequencies, and clinical prognoses to understand their implications for treatment strategies. Additionally, we discuss recent clinical trial efforts targeting this pathway. Understanding the inhibitors currently under clinical investigation may help optimize foundational research and clinical strategies. We hope that elucidating the current status of precision therapeutic stratification for patients targeting the Wnt/ß-catenin pathway will guide future innovations in precision medicine for GICs.
Assuntos
Antineoplásicos , Neoplasias Gastrointestinais , Via de Sinalização Wnt , Humanos , Neoplasias Gastrointestinais/tratamento farmacológico , Neoplasias Gastrointestinais/metabolismo , Via de Sinalização Wnt/efeitos dos fármacos , Via de Sinalização Wnt/fisiologia , Antineoplásicos/uso terapêutico , Antineoplásicos/farmacologia , Animais , beta Catenina/metabolismo , beta Catenina/antagonistas & inibidores , beta Catenina/genética , Terapia de Alvo Molecular/métodosRESUMO
Epidermal growth factor receptor (EGFR) is one of the most studied drug targets for treating non-small-cell lung cancer (NSCLC). However, there are no approved inhibitors for the C797S resistance mutation caused by the third-generation EGFR inhibitor (Osimertinib). Therefore, the development of fourth-generation EGFR inhibitors is urgent. In this study, we clarified the structure-activity relationship of several synthesized compounds as fourth-generation inhibitors against human triple (Del19/T790M/C797S) mutation. Representative compound 52 showed potent inhibitory activity against EGFRL858R/T790M/C797S with an IC50 of 0.55 nM and significantly inhibited the proliferation of the Ba/F3 cell line harboring EGFRL858R/T790M/C797S with an IC50 of 43.28 nM. Moreover, 52 demonstrated good pharmacokinetic properties and excellent in vivo efficacy. Overall, the compound 52 can be considered a promising candidate for overcoming EGFR C797S-mediated mutations.
Assuntos
Acrilamidas , Compostos de Anilina , Antineoplásicos , Carcinoma Pulmonar de Células não Pequenas , Proliferação de Células , Relação Dose-Resposta a Droga , Desenho de Fármacos , Resistencia a Medicamentos Antineoplásicos , Ensaios de Seleção de Medicamentos Antitumorais , Receptores ErbB , Neoplasias Pulmonares , Inibidores de Proteínas Quinases , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Receptores ErbB/genética , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Acrilamidas/farmacologia , Acrilamidas/química , Acrilamidas/síntese química , Relação Estrutura-Atividade , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/síntese química , Compostos de Anilina/farmacologia , Compostos de Anilina/química , Compostos de Anilina/síntese química , Compostos de Anilina/uso terapêutico , Proliferação de Células/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Estrutura Molecular , Animais , Camundongos , Linhagem Celular Tumoral , Mutação , Indóis , PirimidinasRESUMO
OBJECTIVES: To investigate the effects of PLK1 inhibitors on osimertinib-resistant non-small cell lung carcinoma (NSCLC) cells and the anti-tumor effect combined with osimertinib. METHODS: An osimertinib resistant NCI-H1975 cell line was induced by exposure to gradually increasing drug concentrations. Osimertinib-resistant cells were co-treated with compounds from classical tumor pathway inhibitor library and osimertinib to screen for compounds with synergistic effects with osimertinib. The Gene Set Enrichment Analysis (GSEA) was used to investigate the activated signaling pathways in osimertinib-resistant cells; sulforhodamine B (SRB) staining was used to investigate the effect of PLK1 inhibitors on osimertinib-resistant cells and the synergistic effect of PLK1 inhibitors combined with osimertinib. RESULTS: Osimertinib-resistance in NCI-H1975 cell (resistance index=43.45) was successfully established. The PLK1 inhibitors GSK 461364 and BI 2536 had synergistic effect with osimertinib. Compared with osimertinib-sensitive cells, PLK1 regulatory pathway and cell cycle pathway were significantly activated in osimertinib-resistant cells. In NSCLC patients with epidermal growth factor receptor mutations treated with osimertinib, PLK1 mRNA levels were negatively correlated with progression free survival of patients (R=ï¼0.62, P<0.05), indicating that excessive activation of PLK1 in NSCLC cells may cause cell resistant to osimertinib. Further in vitro experiments showed that IC50 of PLK1 inhibitors BI 6727 and GSK 461364 in osimertinib-resistant cells were lower than those in sensitive ones. Compared with the mono treatment of osimertinib, PLK1 inhibitors combined with osimertinib behaved significantly stronger effect on the proliferation of osimertinib-resistant cells. CONCLUSIONS: PLK1 inhibitors have a synergistic effect with osimertinib on osimertinib-resistant NSCLC cells which indicates that they may have potential clinical value in the treatment of NSCLC patients with osimertinib resistance.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Receptores ErbB/genética , Receptores ErbB/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/genética , Mutação , Linhagem Celular TumoralRESUMO
BACKGROUND AND AIMS: Succinate dehydrogenase enzyme (SDH) is frequently diminished in samples from patients with hepatocellular carcinoma (HCC), and SDH reduction is associated with elevated succinate level and poor prognosis in patients with HCC. However, the underlying mechanisms of how impaired SDH activity promotes HCC remain unclear. APPROACH AND RESULTS: In this study, we observed remarkable downregulations of SDH subunits A and B (SDHA/B) in chronic liver injury-induced murine HCC models and patient samples. Subsequent RNA sequencing, hematoxylin and eosin staining, and immunohistochemistry analyses of HCC samples revealed that Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) were significantly upregulated in HCC, with their levels inversely correlating with that of SDHA/B. YAP/TAZ stability was greatly enhanced in SDHA/B-depleted HCC cells along with accumulation of succinate. Further mechanistic analyses demonstrated that impaired activity of SDHA/B resulted in succinate accumulation, which facilitated the deNEDDylation of cullin1 and therefore disrupted the E3 ubiquitin ligase SCF ß-TrCP complex, consequently leading to YAP/TAZ stabilization and activation in HCC cells. The accelerated in vitro cell proliferation and in vivo tumor growth caused by SDHA/B reduction or succinate exposure were largely dependent on the aberrant activation of YAP/TAZ. CONCLUSIONS: Our study demonstrated that SDHA/B reduction promotes HCC proliferation by preventing the proteasomal degradation of YAP/TAZ through modulating cullin1 NEDDylation, thus binding SDH-deficient HCC cells to YAP/TAZ pathway and rendering these cells vulnerable to YAP/TAZ inhibition. Our findings warrant further investigation on the therapeutic effects of targeting YAP/TAZ in patients with HCC displaying reduced SDHA/B or elevated succinate levels.
Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Animais , Camundongos , Carcinoma Hepatocelular/patologia , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Neoplasias Hepáticas/patologia , Transativadores/metabolismo , Proteínas de Sinalização YAP , Succinatos , Complexo II de Transporte de Elétrons/metabolismoRESUMO
INTRODUCTION: Cholangiocarcinoma consists of a cluster of malignant biliary tumors that tend to have a poor prognosis, ranking as the second most prevalent type of liver cancer, and their incidence rate has increased globally recently. The high-frequency driving mutations of cholangiocarcinoma, such as KRAS/IDH1/ARID1A/P53, imply the epigenetic instability of cholangiocarcinoma, leading to the dysregulation of various related transcription factors, thus affecting the occurrence and development of cholangiocarcinoma. Increasingly evidence indicates that the high heterogeneity and malignancy of cholangiocarcinoma are closely related to the dysregulation of transcription factors which promote cell proliferation, invasion, migration, angiogenesis, and drug resistance through reprogrammed transcriptional networks. It is of great significance to further explore and summarize the role of transcription factors in cholangiocarcinoma. AREAS COVERED: This review summarizes the oncogenic or tumor suppressive roles of key transcription factors in regulating cholangiocarcinoma progression and the potential targeting strategies of transcription factors in cholangiocarcinoma. EXPERT OPINION: Cholangiocarcinoma is a type of cancer highly influenced by transcriptional regulation, specifically transcription factors and epigenetic regulatory factors. Targeting transcription factors could be a potential and important strategy that is likely to impact future cholangiocarcinoma treatment.
Assuntos
Neoplasias dos Ductos Biliares , Colangiocarcinoma , Neoplasias Hepáticas , Humanos , Neoplasias dos Ductos Biliares/tratamento farmacológico , Neoplasias dos Ductos Biliares/genética , Colangiocarcinoma/tratamento farmacológico , Colangiocarcinoma/genética , Fatores de Transcrição/genética , Neoplasias Hepáticas/patologia , Ductos Biliares Intra-Hepáticos/metabolismo , Ductos Biliares Intra-Hepáticos/patologiaRESUMO
BACKGROUND: Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths worldwide. Sorafenib is the first-line treatment for advanced HCC, but the anti-cancer effects remain to be improved as indicated by its low response rates and failure to prolong the progression-free survival (PFS). Thus, it is urgent to explore approaches to improve the clinical outcome. MATERIALS AND METHODS: The effect of Sorafenib in HCC was analyzed by SRB (sulforhodamine B) assay in normoxia and hypoxia, respectively. The different dose combination effect of CT707 and sorafenib was analyzed by SRB assay in hypoxia. Flow cytometry assay was used to detect the cell apoptosis rate with CT707 and sorafenib treatment in hypoxia. Western blotting was used to detect the expression levels of apoptosis -related proteins and the mechanism of CT707 overcome the resistance of sorafenib in hypoxia. RESULTS: Our study showed that the characteristic intratumor hypoxia of advanced HCC is one of the major factors which mediated the drug resistance towards sorafenib in HCC. And CT-707, a novel multi-kinase inhibitor, could sensitize the hypoxic HCC cells towards sorafenib. Further studies showed that CT-707 abolished the nuclear translocation of Yes Associate-Protein (YAP), which has been demonstrated as one of mechanism of hypoxia-mediated sorafenib-resistance in HCC. CONCLUSIONS: Overall, this study not only favors the development of this novel multi-kinase inhibitor CT-707 as a therapeutic agent against HCC, but also provides a potential strategy to overcome the hypoxia-mediated resistance to sorafenib in HCC patients.
Assuntos
Antineoplásicos , Carcinoma Hepatocelular , Neoplasias Hepáticas , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Humanos , Hipóxia , Neoplasias Hepáticas/patologia , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas , Pirróis , Sorafenibe/farmacologia , Sorafenibe/uso terapêutico , SulfonamidasRESUMO
The gain of cell motility is an essential prerequisite for cancer metastasis. The ubiquitin ligase subunit WD repeat and SOCS box-containing 1 (WSB1) has been demonstrated to regulate hypoxia-driven tumor cell migration. However, there is still a lack of methods for discovering inhibitors targeting the WSB1 axis. Here, we employed phenotypic screening models and identified compound 4 that displayed migration inhibitory activity against WSB1-overexpressing cells. Further studies indicated that it may function as a WSB1 degrader, thus leading to the accumulation of the Rho guanosine diphosphate dissociation inhibitor 2 (RhoGDI2) protein, reversing the expression of downstream F-actin and formation of membrane ruffles, and disturbing the migration capacity of cancer cells. Moreover, compound 4 exhibited a promising in vivo anticancer metastatic effects. Our findings show the discovery of a new WSB1 degrader, providing a unique solution for the treatment of cancer metastasis.
Assuntos
Aminopiridinas/uso terapêutico , Antineoplásicos/uso terapêutico , Movimento Celular/efeitos dos fármacos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Metástase Neoplásica/tratamento farmacológico , Neoplasias/tratamento farmacológico , Aminopiridinas/síntese química , Aminopiridinas/farmacocinética , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacocinética , Linhagem Celular Tumoral , Feminino , Humanos , Masculino , Camundongos Endogâmicos BALB C , Estrutura Molecular , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
Cholangiocarcinoma (CCA) has emerged as an intractable cancer with scanty therapeutic regimens. The aberrant activation of Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) are reported to be common in CCA patients. However, the underpinning mechanism remains poorly understood. Deubiquitinase (DUB) is regarded as a main orchestrator in maintaining protein homeostasis. Here, we identified Josephin domain-containing protein 2 (JOSD2) as an essential DUB of YAP/TAZ that sustained the protein level through cleavage of polyubiquitin chains in a deubiquitinase activity-dependent manner. The depletion of JOSD2 promoted YAP/TAZ proteasomal degradation and significantly impeded CCA proliferation in vitro and in vivo. Further analysis has highlighted the positive correlation between JOSD2 and YAP abundance in CCA patient samples. Collectively, this study uncovers the regulatory effects of JOSD2 on YAP/TAZ protein stabilities and profiles its contribution in CCA malignant progression, which may provide a potential intervention target for YAP/TAZ-related CCA patients.
RESUMO
Aberrant activation of the RAS superfamily is one of the critical factors in carcinogenesis. Among them, KRAS is the most frequently mutated one which has inspired extensive studies for developing approaches to intervention. Although the cognition toward KRAS remains far from complete, mounting evidence suggests that a variety of post-translational modifications regulate its activation and localization. In this review, we summarize the regulatory mode of post-translational modifications on KRAS including prenylation, post-prenylation, palmitoylation, ubiquitination, phosphorylation, SUMOylation, acetylation, nitrosylation, etc. We also highlight the recent studies targeting these modifications having exhibited potent anti-tumor activities.
Assuntos
Processamento de Proteína Pós-Traducional/fisiologia , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Sequência de Aminoácidos , Animais , Humanos , Processamento de Proteína Pós-Traducional/efeitos dos fármacosRESUMO
Dysregulated transcription factors (TFs) fuel aberrant gene expression networks, resulting in cell overproliferation, migration, and immunosuppression. Given that TFs are regarded to have vital roles in tumors, various approaches are exploited to modulate their activities. Nevertheless, except for some ligand-binding nuclear receptors, most TFs are still considered 'undruggable' targets. Responding to extra- or intracellular stimuli, TFs are decorated with an array of post-translational modifications (PTMs) to regulate their subcellular localizations, protein-protein/DNA interactions, and stability. These PTMs orchestrate the multiple functions of TFs, thus offering numerous potential targets. In this review, we systematically review emerging concepts and effective agents in PTMs-associated TF-targeting, which could provide paradigms for cancer treatment.
Assuntos
Neoplasias/tratamento farmacológico , Processamento de Proteína Pós-Traducional , Fatores de Transcrição/metabolismo , Acetilação , Animais , Humanos , Metilação , Neoplasias/metabolismo , FosforilaçãoRESUMO
Yes-associated protein (YAP) and its paralog, transcriptional coactivator with PDZ-binding motif (TAZ), play pivotal roles in promoting the progression of hepatocellular carcinoma. However, the regulatory mechanism underpinning aberrant activation of YAP/TAZ in hepatocellular carcinoma remains unclear. In this study, we globally profiled the contribution of deubiquitinating enzymes (DUB) to both transcriptional activity and protein abundance of YAP/TAZ in hepatocellular carcinoma models and identified ubiquitin-specific peptidase 10 (USP10) as a potent YAP/TAZ-activating DUB. Mechanistically, USP10 directly interacted with and stabilized YAP/TAZ by reverting their proteolytic ubiquitination. Depletion of USP10 enhanced polyubiquitination of YAP/TAZ, promoted their proteasomal degradation, and ultimately arrested the proliferation of hepatocellular carcinoma in vitro and in vivo. Expression levels of USP10 positively correlated with the abundance of YAP/TAZ in hepatocellular carcinoma patient samples as well as in N-nitrosodiethylamine (DEN)-induced liver cancer mice models. Collectively, this study establishes the causal link between USP10 and hyperactivated YAP/TAZ in hepatocellular carcinoma cells and provides a rationale for potential therapeutic interventions in the treatment of patients with hepatocellular carcinoma harboring a high level of YAP/TAZ. SIGNIFICANCE: These findings identify USP10 as a DUB of YAP/TAZ and its role in hepatocellular carcinoma progression, which may serve as a potential therapeutic target for hepatocellular carcinoma treatment.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/metabolismo , Transativadores/metabolismo , Fatores de Transcrição/metabolismo , Ubiquitina Tiolesterase/metabolismo , Animais , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Proliferação de Células/fisiologia , Feminino , Células HEK293 , Células Hep G2 , Xenoenxertos , Humanos , Neoplasias Hepáticas/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Nus , Transdução de Sinais , Proteínas com Motivo de Ligação a PDZ com Coativador Transcricional , Proteínas de Sinalização YAPRESUMO
Aldo-keto reductase family 1 member C1 (AKR1C1) promotes malignancy of Non-Small Cell Lung Cancer (NSCLC) by activating Signal Transducer and Activator of Transcription 3 (STAT3) pathway. However, how the pro-metastatic functions of AKR1C1 are switched on/off remains unknown. Methods: Immunoprecipitation and LC-MS/MS analyses were performed to identify the acetylation on AKR1C1 protein, and the functional analyses (in vitro and in vivo) were performed to depict the contribution of acetylation to the pro-metastatic effects of AKR1C1. Results: Here we report that acetylated AKR1C1 on two lysine residues K185 & K201 is critical to its pro-metastatic role. The acetylation modification has no impact on the canonical enzymatic activity of AKR1C1, while it is required for the interaction between AKR1C1 to STAT3, which triggers the downstream transduction events, ultimately mobilizing cells. Importantly, the deacetylase Sirtuin 2 (SIRT2) is capable of deacetylating AKR1C1, inhibiting the transactivation of STAT3 target genes, thus suppressing the migration of cells. Conclusion: Acetylation on Lysines 185 and 201 of AKR1C1 dictates its pro-metastatic potential both in vitro and in vivo, and the reverting of acetylation by Sirtuin 2 provides potential therapeutic targets for treatment against metastatic NSCLC patients with high AKR1C1 expression.
Assuntos
20-Hidroxiesteroide Desidrogenases/metabolismo , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Neoplasias Pulmonares/patologia , Sirtuína 2/metabolismo , 20-Hidroxiesteroide Desidrogenases/química , Acetilação , Animais , Carcinógenos/metabolismo , Carcinoma Pulmonar de Células não Pequenas/terapia , Movimento Celular/efeitos dos fármacos , Movimento Celular/genética , Modelos Animais de Doenças , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Metástase Neoplásica/genética , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais , Sirtuína 2/químicaRESUMO
Hepatocellular carcinoma (HCC) has emerged as one of the most prevalent life-threatening cancers, and the high mortality rate is largely due to the metastasis. The sustained activation of Smad4 and transforming growth factor-ß (TGF-ß) is closely associated with advanced HCC metastasis. However, the regulatory mechanism underlying the aberrant activation of Smad4 and TGF-ß pathway remains elusive. In this study, using a functional screen of USPs siRNA library, we identified ubiquitin-specific proteases USP10 as a deubiquitinating enzyme (DUB) that sustains the protein level of Smad4 and activates TGF-ß signaling. Further analysis showed that USP10 directly interacts with Smad4 and stabilizes it through the cleavage of its proteolytic ubiquitination, thus promoting HCC metastasis. The suppression of USP10 by either shRNAs or catalytic inhibitor Spautin-1 significantly inhibited the migration of HCC cells, whereas the reconstitution of Smad4 was able to efficiently rescue this defect. Overall, our study not only uncovers the regulatory effect of USP10 on the protein abundance of Smad4, but also indicates that USP10 could be regarded as a potential intervention target for the metastatic HCC in Smad4-positive patients.
Assuntos
Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/metabolismo , Proteína Smad4/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Ubiquitina Tiolesterase/metabolismo , Ubiquitinação/genética , Animais , Benzilaminas/farmacologia , Carcinoma Hepatocelular/enzimologia , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/secundário , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Movimento Celular/genética , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Humanos , Neoplasias Hepáticas/enzimologia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Ligação Proteica , Estabilidade Proteica , Quinazolinas/farmacologia , RNA Interferente Pequeno , Proteína Smad4/genética , Ubiquitina Tiolesterase/antagonistas & inibidores , Ubiquitina Tiolesterase/genética , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: Yes-associated protein (YAP) is a key effector of the Hippo pathway and is frequently dysregulated in aggressive human cancers. Aberrant YAP activation has emerged as an important driver of tumorigenesis, chemoresistance and metastasis. Since posttranslational modifications (PTMs) are pivotal modifiers that determine protein activation or subcellular localization, the malfunction of YAP due to dysregulated PTMs has been linked to various cancers. Collectively, although YAP has long been considered an "undruggable" transcription cofactor, its PTMs may be its "Achilles' heel". To provide theoretical support for developing small molecule inhibitors based on PTMs, in this review article, we summarize the current understanding of the impact of PTMs in regulating the Hippo-YAP pathway and further discuss potential therapeutic intervention. SCOPE OF REVIEW: In our review, we summarize the known posttranslational modifications (PTMs) of YAP that dictate its protein stability, transcriptional activity and subcellular localization at different stages. Here, we clearly summarize the specific enzymes and sites involved in YAP PTMs and place additional focus on the consequences of PTM-modulated YAP activity and translocation. MAIN CONCLUSION: PTMs of YAP play fundamental roles in controlling the protein abundance and function. Therefore, interfering with PTMs of YAP may contribute to solving the "undruggable" problem in YAP inhibition, thus providing new approaches for YAP-based cancer therapy. GENERAL SIGNIFICANCE: Future studies that target corresponding PTM-related kinases/enzymes will provide new strategies for cancer therapy, particularly in tumors with YAP dysregulation.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Carcinogênese/genética , Neoplasias/genética , Proteínas Serina-Treonina Quinases/genética , Fatores de Transcrição/genética , Resistencia a Medicamentos Antineoplásicos/genética , Via de Sinalização Hippo , Humanos , Metástase Neoplásica , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Processamento de Proteína Pós-Traducional/genética , Transdução de Sinais/genética , Proteínas de Sinalização YAPRESUMO
Dysfunction or dysregulation of the ubiquitin proteasome system (UPS) is closely related to tumorigenesis and the development of multiple cancers. Targeting the UPS provides a new anticancer therapeutic strategy, but clinically available UPS-targeted inhibitors, including lenalidomide and bortezomib, are limited to treat solid tumors. Under physiological conditions, deubiquitinases or deubiquitinating enzymes (DUBs) play vital roles in the UPS by removing ubiquitin from substrate proteins and regulating their proteasomal degradation and sub-localization, thus maintaining the balance between ubiquitination and deubiquitination for protein quality control and homeostasis. The aberrant expression or function of DUBs generally leads to the occurrence and progression of a series of disorders, including malignant tumors. Therefore, targeting DUBs is a novel anticancer therapeutic strategy. Ubiquitin-specific proteases (USPs) are the largest subfamily of DUBs which have attracted considerable interest as anticancer targets. Most of USPs are abnormally activated or expressed in a variety of malignant tumors or in the tumor microenvironment, making them ideal anticancer target candidates, which indicates that USPs inhibitors may be a class of potential anticancer therapeutic agents. However, there are no relevant inhibitors targeting USPs have entered clinical trial so far. In this review, we will summarize the roles and mechanisms of USPs in malignant transformation and progression as well as recent advances of small-molecule inhibitors targeting USPs.
RESUMO
Given that Yes-associated protein (YAP) signaling acts as a critical survival input for hypoxic cancer cells in hepatocellular carcinoma (HCC), disruption of YAP function and the maintenance of hypoxia is an attractive way to treat HCC. Utilizing a cell-based YAP-TEAD luciferase reporter assay and functional analyses, we identified CT-707, a China-FDA approved multi-kinase inhibitor under clinical trial with remarkable inhibitory activity against YAP function. CT-707 exhibited prominent cytotoxicity under hypoxia on HCC cells, which was attributable to the inhibition of YAP signaling. CT-707 arrested tumor growth in HepG2, Bel-7402, and HCC patient-derived xenografts. Mechanistically, the inhibitory activity of CT-707 on YAP signaling was due to the interruption of hypoxia-activated IGF1R. Overall, these findings not only identify CT-707 as a promising hypoxia-targeting agent against HCC, but they also unveil IGF1R as a new modulator specifically regulating hypoxia-activated YAP signaling.Significance: CT-707 may represent a novel clinical approach for patients with HCC suffering poor drug response due to intratumor hypoxia. Cancer Res; 78(14); 3995-4006. ©2018 AACR.
Assuntos
Hipóxia/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/metabolismo , Proteínas Nucleares/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Receptor IGF Tipo 1/metabolismo , Fatores de Transcrição/metabolismo , Animais , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/metabolismo , Proteínas de Ciclo Celular , Linhagem Celular Tumoral , China , Citotoxinas/farmacologia , Células Hep G2 , Humanos , Hipóxia/metabolismo , Camundongos , Camundongos Nus , Transdução de Sinais/efeitos dos fármacosRESUMO
Metastasis is the leading cause of mortality for human non-small cell lung cancer (NSCLC). However, it is difficult to target tumor metastasis because the molecular mechanisms underlying NSCLC invasion and migration remain unclear. Methods: GEO data analyses and IHC analyses were performed to identify that the expression level of AKR1C1, a member of human aldo-keto reductase family, was highly elevated in patients with metastasis or metastatic foci of NSCLC patients. Functional analyses (in vitro and in vivo) and quantitative genomic analyses were preformed to confirm the pro-metastatic effects of AKR1C1 and the underlying mechanisms. The correlation of AKR1C1 with the prognosis of NSCLC patients was evaluated using Kaplan-Meier analyses. Results: in NSCLC patients, AKR1C1 expression was closely correlated with the metastatic potential of tumors. AKR1C1 overexpression in nonmetastatic cancer cells significantly promoted metastasis both in vitro and in vivo, whereas depletion of AKR1C1 in highly metastatic tumors potently alleviated these effects. Quantitative genomic and functional analyses revealed that AKR1C1 directly interacted with STAT3 and facilitated its phosphorylation-thus reinforcing the binding of STAT3 to the promoter regions of target genes-and then transactivated these genes, which ultimately promoted tumor metastasis. Further studies showed that AKR1C1 might facilitate the interaction of STAT3 with its upstream kinase JAK2. Intriguingly, AKR1C1 exerted these pro-metastatic effects in a catalytic-independent manner. In addition, a significant correlation between AKR1C1 and STAT3 pathway was observed in the metastatic foci of NSCLC patients, and the AKR1C1-STAT3 levels were highly correlated with a poor prognosis in NSCLC patients. Conclusions: taken together, we show that AKR1C1 is a potent inducer of NSCLC metastasis. Our study uncovers the active function of AKR1C1 as a key component of the STAT3 pathway, which promotes lung cancer metastasis, and highlights a candidate therapeutic target to potentially improve the survival of NSCLC patients with metastatic disease.
Assuntos
20-Hidroxiesteroide Desidrogenases/metabolismo , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Neoplasias Pulmonares/metabolismo , 20-Hidroxiesteroide Desidrogenases/genética , Animais , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Células HEK293 , Humanos , Janus Quinase 2/metabolismo , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Nus , Metástase Neoplásica , Fator de Transcrição STAT3/metabolismoRESUMO
Gold nanorods (AuNRs) are suitable candidates for photothermal therapy in vivo, because of their excellent ability to transfer near-infrared (NIR) light into heat. However, appropriate surface should be generated on AuNRs before their in vivo application because of the low colloidal stability in complicate biological environment and relatively strong toxicity compared to their pristine stabilizer cetyltrimethylammonium bromide. In the current study, polysarcosine (PS), a non-ionic hydrophilic polypeptoid whose structure is similar to polypeptides, bearing repeating units of natural α-amino acid, was used to stabilize AuNRs due to its excellent hydrophilicity and biocompatibility. Polysarcosine with optimized molecular weight was synthesized and used to modify AuNRs by traditional ligand exchange. The grafting of PS on AuNRs was evidenced by fourier transform infrared (FTIR) spectroscopy and the alternation of surface zeta potential. The polysarcosine coated AuNRs (Au@PS) showed good stabilities in wide pH range and simulated physiological buffer with the ligand competition of dithiothreitol (DTT). The Au@PS NRs had neglectable cytotoxicity and showed efficient ablation of tumor cells in vitro. Moreover, Au@PS NRs had a longer circulation time in body that resulted in a higher accumulation in solid tumors after intravenous injection, compared to AuNRs capped with polyethylene glycol (PEG). Photothermal therapy in vivo demonstrated that the tumors were completely destroyed by single-time irradiation of NIR laser after one-time injection of the polysarcosine capped AuNRs. The Au@PS NRs did not cause obvious toxicity in vivo, suggesting promising potential in cancer therapy. STATEMENT OF SIGNIFICANCE: In current study, polysarcosine (PS), a non-ionic hydrophilic polypeptoid whose structure is similar to polypeptides, bearing repeating units of natural α-amino acid, was used to stabilize AuNRs due to its excellent hydrophilicity and biocompatibility. The polysarcosine coated AuNRs (Au@PS) showed good stabilities in wide pH range and simulated physiological buffer. The Au@PS NRs had very low cytotoxicity and showed high efficacy for the ablation of cancer cells in vitro. Moreover, Au@PS NRs had a longer circulation time in blood that led to a higher accumulation in tumors after intravenous injection, compared to AuNRs capped with polyethylene glycol (PEG). In vivo photothermal therapy showed that tumors were completely cured without reoccurrence by one-time irradiation of NIR laser after a single injection of the polysarcosine modified AuNRs.
Assuntos
Ouro/química , Hipertermia Induzida , Nanotubos/química , Neoplasias/terapia , Peptídeos/química , Fototerapia , Sarcosina/análogos & derivados , Células A549 , Animais , Materiais Biocompatíveis/farmacologia , Circulação Sanguínea , Sobrevivência Celular , Coloides/química , Ligantes , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Microscopia de Fluorescência , Nanotubos/ultraestrutura , Neoplasias/patologia , Sarcosina/química , Espectrofotometria Ultravioleta , Espectroscopia de Infravermelho com Transformada de Fourier , Espectroscopia de Luz Próxima ao Infravermelho , Distribuição Tecidual , Carga Tumoral , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Hepatocellular carcinoma is among the leading causes of cancer-related deaths worldwide, and the development of new treatment regimens is urgently needed to improve therapeutic approach. In our study, we found that the combination of a Met inhibitor, cabozantinib, and a novel FAK inhibitor, CT-707, exerted synergistic antitumor effects against hepatocellular carcinoma in vitro and in vivo Interestingly, further studies showed that therapeutic concentrations of cabozantinib increased the phosphorylation of FAK, which might attenuate the antitumor activity of cabozantinib. The simultaneous exposure to CT-707 effectively inhibited the activation of FAK that was induced by cabozantinib, which contributes to the synergistic effect of the combination. Furthermore, cabozantinib increased the mRNA and protein levels of integrin α5, which is a canonical upstream of FAK, and the introduction of cilengitide to block integrin function could abrogate FAK activation by cabozantinib, indicating that cabozantinib upregulated the phosphorylation of FAK in an integrin-dependent manner. Similar synergy was also observed on PHA-665752, another selective MET inhibitor, indicating that this observation might be a common characteristic of MET-targeting strategies. Our findings not only favor the development of the novel FAK inhibitor CT-707 as a therapeutic agent against hepatocellular carcinoma but also provide a new strategy of combining MET and FAK inhibitors to potentiate the anticancer activities of these two types of agents for treating hepatocellular carcinoma patients. Mol Cancer Ther; 15(12); 2916-25. ©2016 AACR.