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BACKGROUND/AIM: Metastatic lymph node 64 (MLN64) is often co-amplified with ERBB2 (HER2) and plays a role in the progression of breast and prostate cancer. The present study explored the expression of MLN64 in clinical gastric cancer in association with the ERBB family and its impact on drug resistance in patients. MATERIALS AND METHODS: Two independent gastric cancer cohorts (n=324; n=87) were used to explore the expression profile of MLN64 in conjunction with ERBB family members in clinical gastric cancer and its association with neoadjuvant chemotherapy responses. Gastric cancer AGS and HCG27 cells with MLN64 knockdown were generated to determine the function of MLN64 in cell behavioural changes. RESULTS: Gastric tumor tissues expressed significantly higher levels of MLN64 compared with normal tissues (p<0.01); however, MLN64 alone was a weak prognostic indicator. An integrated co-expression of MLN64, ERBB4, and NRG4 was a significant factor in assessing overall survival in both cohorts. MLN64 was a profound indicator of patient response to neoadjuvant chemotherapy. In vitro studies indicated a significant contribution of MLN64 to the response of gastric cancer cells to chemodrugs and Her-2 inhibitors. MLN64 knockdown also contributed to the adhesion and migration and suggested a possible mechanism mediated by the interaction between MLN64 and ERBBs. CONCLUSION: MLN64 is an indicator of patient response to neoadjuvant chemotherapy in gastric cancer. Together with the expression pattern of ERBB4, MLN64 is a poor prognostic factor for patients with gastric cancer.
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Neoplasias Gástricas , Humanos , Masculino , Resistência a Medicamentos , Linfonodos , Prognóstico , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/genéticaRESUMO
Objective: Striatins (STRNs) family, which contains three multi-domain scaffolding proteins, are cornerstones of the striatins interacting phosphatase and kinase (STRIPAK) complex. Although the role of the STRIPAK complex in cancer has become recognized in recent years, its clinical significance in breast cancer has not been fully established. Methods: Using a freshly frozen breast cancer tissue cohort containing both cancerous and adjacent normal mammary tissues, we quantitatively evaluated the transcript-level expression of all members within the STRIPAK complex along with some key interacting and regulatory proteins of STRNs. The expression profile of each molecule and the integrated pattern of the complex members were assessed against the clinical-pathological factors of the patients. The Cancer Genome Atlas (TCGA) dataset was used to evaluate the breast cancer patients' response to chemotherapies. Four human breast cancer cell lines, MDA-MB-231, MDA-MB-361, MCF-7, and SK-BR-3, were subsequently adopted for in vitro work. Results: Here we found that high-level expressions of STRIP2, calmodulin, CCM3, MINK1 and SLMAP were respectively associated with shorter overall survival (OS) of patients. Although the similar pattern observed for STRN3, STRN4 and a contrary pattern observed for PPP2CA, PPP2CB and PPPR1A were not significant, the integrated expression profile of STRNs group and PPP2 group members constitutes a highly significant prognostic indicator for OS [P<0.001, hazard ratio (HR)=2.04, 95% confidence interval (95% CI), 1.36-3.07] and disease-free survival (DFS) (P=0.003, HR=1.40, 95% CI, 1.12-1.75). Reduced expression of STRN3 has an influence on the biological functions including adhesiveness and migration. In line with our clinical findings, the breast cancer cells responded to STRN3 knockdown with changes in their chemo-sensitivity, of which the response is also breast cancer subtype dependent. Conclusions: Our results suggest a possible role of the STRIPAK complex in breast cancer development and prognosis. Among the members, the expression profile of STRN3 presents a valuable factor for assessing patients' responses to drug treatment.
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BACKGROUND/AIM: Claudin-10 (CLDN10) is a membrane integral protein. It is one of the widely expressed tight junctional claudins with functions not well defined. In the present study, the expression profile and its role in cerebral endothelial cells and in the interaction between breast cancer and endothelial cells were investigated. MATERIALS AND METHODS: CLDN10 expression was examined in a wide range of cell types. Brain endothelial cell models with or without CLDN10 expression were generated using the hCMEC/D3 cell line and used to test the barrier and permeability functions. Transendothelial drug delivery and invasion were also evaluated. RESULTS: hCMEC/D3 cells express high levels of CLDN10, compared with peripheral endothelial cells, mesothelial cells, fibroblasts, and breast cancer cells, which were either negative or expressed low levels of CLDN10. Knockdown of CLDN10 in hCMEC/D3 cells resulted in impaired tight junctions as seen by reduced transendothelial electric resistance and paracellular permeability. It also accelerated invasion of breast cancer cells through the endothelial cell layer. CLDN10 knockdown in hCMEC/D3 cells led to an increase in transendothelial chemodrug delivery. Furthermore, the SRC kinase inhibitor (AZM475271) was able to decrease the impedance and increase the paracellular permeability in cerebral endothelial cells. CONCLUSION: Cerebral endothelial cells express high levels of CLDN10, a protein regulating barrier function and thereby drug permeability and cancer invasiveness in brain endothelial cells, suggesting that it is a novel therapeutic target for the treatment of brain metastasis-related diseases.
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Neoplasias Encefálicas , Neoplasias da Mama , Humanos , Feminino , Células Endoteliais , Barreira Hematoencefálica , Neoplasias da Mama/genética , Claudinas/genética , Neoplasias Encefálicas/genéticaRESUMO
Activated Leukocyte Cell Adhesion Molecule (ALCAM/CD166) is a cell-cell adhesion protein conferring heterotypic and homotypic interactions between cells of the same type and different types. It is aberrantly expressed in various cancer types and has been shown to be a regulator of cancer metastasis. In the present study, we investigated potential roles of ALCAM in the peritoneal transcoelomic metastasis in gastrointestinal cancers, a metastatic type commonly occurred in gastro-intestinal and gynaecological malignancies and resulting in poor clinical outcomes. Specifically, we studied whether ALCAM acts as both a 'seed' receptor in these tumour cells and a 'soil' receptor in peritoneal mesothelial cells during cancer metastasis. Gastric cancer and pancreatic cancer tissues with or without peritoneal metastasis were compared for their levels of ALCAM expression. The impact of ALCAM expression in these tumours was also correlated to the patients' clinical outcomes, namely peritoneal metastasis-free survival. In addition, cancer cells of gastric and pancreatic origins were used to create cell models with decreased or increased levels of ALCAM expression by genetic knocking down or overexpression, respectively. Human peritoneal mesothelial cells were also genetically transfected to generate cell models with different profiles of ALCAM expression. These cell models were used in the tumour-mesothelial interaction assay to assess if and how the interaction was influenced by ALCAM. Both gastric and pancreatic tumour tissues from patients who developed peritoneal metastases had higher levels of ALCAM transcript than those without. Patients who had tumours with high levels of ALCAM had a much shorter peritoneal metastasis free survival compared with those who had low ALCAM expression (p = 0.006). ALCAM knockdown of the mesothelial cell line MET5A rendered the cells with reduced interaction with both gastric cancer cells and pancreatic cancer cells. Likewise, levels of ALCAM in both human gastric and pancreatic cancer cells were also a determining factor for their adhesiveness to mesothelial cells, a process that was likely to be triggered the phosphorylation of the SRC kinase. A soluble ALCAM (sALCAM) was found to be able to inhibit the adhesiveness between cancer cells and mesothelial cells, mechanistically behaving like a SRC kinase inhibitor. ALCAM is an indicator of peritoneal metastasis in both gastric and pancreatic cancer patients. It acts as not only a potential peritoneal 'soil' receptor of tumour seeding but also a 'soil' receptor in peritoneal mesothelial cells during cancer metastasis. These findings have an important therapeutic implication for treating peritoneal transcoelomic metastases.
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Molécula de Adesão de Leucócito Ativado , Neoplasias Pancreáticas , Neoplasias Peritoneais , Neoplasias Gástricas , Humanos , Molécula de Adesão de Leucócito Ativado/genética , Molécula de Adesão de Leucócito Ativado/metabolismo , Adesão Celular , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Quinases da Família src/metabolismo , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Neoplasias Peritoneais/secundário , Neoplasias PancreáticasRESUMO
Death associated protein3 (DAP3) was identified as a responsive protein to interferongammainduced cell death which possibly exerts this regulation by interacting with DAP3 binding cell Death enhancer1 (DELE1), a newly discovered mitochondrial stress protein in response to cell stress signals. Whilst DAP3 has been shown to be aberrantly expressed in several cancer types (i.e. breast cancer), little is known about the relationship between DAP3 and DELE1 in cancers. The present study examined the expression levels of both DAP3 and DELE1 in clinical colorectal cancers (CRCs), as well as their implication on chemoresistance and mechanism behind the action. Firstly, transcript levels of both DAP3 and DELE1 were quantitatively assessed in a clinical cohort of CRC (n=94). Tumour tissues had significantly higher levels of DAP3, but not DELE1 compared with normal tissues. Levels of DAP3 and DELE1 had a significant association with patient's clinical outcomes and local recurrence. DAP3 and DELE1 significantly correlated in normal colorectal tissues but not in tumour tissues. Secondly, the protein levels of DAP3 and DELE1 were evaluated in both normal and tumour colon tissues which showed that both proteins were highly aberrant in CRC tissues. In addition, both DAP3 and DELE1 at transcript and protein levels were identified as prognostic factors for patient's clinical outcomes. Furthermore, in in vitro assays, knocking down DAP3 or DELE1, and in particular both DAP3 and DELE1 together rendered the CRC cells more sensitive to chemotherapy drugs, consistent with clinical findings of the TCGACOAD datasets. The acquisition of drug sensitivity following the genetic knockdown was independent of the mitochondrial metabolism, as neither DAP3 knockdown nor DELE1 knockdown showed a significant change. In summary, DAP3 and DELE1 are highly aberrant in CRCs, and both molecules are prognostic factors for patient's clinical outcomes and local recurrence, and are indicators for chemoresistance.
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Proteínas Reguladoras de Apoptose , Neoplasias Colorretais , Humanos , Proteínas Reguladoras de Apoptose/genética , Morte Celular , Linhagem Celular Tumoral , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Resistencia a Medicamentos Antineoplásicos/genética , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismo , Proteínas de Ligação a RNARESUMO
OBJECTIVE: Sorafenib is a first-line drug for advanced hepatocellular carcinoma (HCC). Unfortunately, most patients with HCC do not respond to sorafenib, mainly because of the frequent development of drug resistance. Bilirubin is an end metabolite of heme catabolism and an indicator of liver function, but its direct role in regulating the anticancer activity of sorafenib in HCC cells is unclear. In the current study, we aimed to investigate the mechanism of action of bilirubin in sorafenib-mediated tumor suppression in HCC. METHODS: A retrospective observational cohort of 100 patients receiving sorafenib was conducted to evaluate the potential role of bilirubin in predicting the prognosis of patients with HCC. Human HCC cell lines were treated with sorafenib in the absence or presence of bilirubin, and cell proliferation, apoptosis, and signaling pathways were assayed. The antagonistic effect of bilirubin toward sorafenib was assessed in nude mice bearing HCC xenografts. RESULTS: Serum levels of bilirubin (including total, direct, and indirect bilirubin) negatively correlated with the overall survival of patients with HCC treated with sorafenib (P < 0.05). Both in vitro and in vivo analyses demonstrated that bilirubin significantly abrogated sorafenib-mediated proliferation inhibition and apoptosis induction in HCC cells (P < 0.05). Mechanically, bilirubin inhibited sorafenib-induced activation of GSK-3ß and subsequent downstream MCL-1 degradation. CONCLUSIONS: Our study provides experimental evidence of the antagonistic effect of bilirubin toward sorafenib-mediated anticancer activity in HCC, and it suggests that bilirubin could be used to predict the efficacy of sorafenib treatmen.
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Benzo[a]pyrene (BaP) can cause hepatorenal toxicity. Secoisolariciresinol diglucoside (SDG), a polyphenolic compound present in flaxseed, has shown a variety of biological activities including antioxidant, anti-inflammatory, anti-apoptotic effects. This study aimed to investigate the protective effects and working mechanisms of SDG against BaP-induced hepatorenal injury. Forty male mice were administrated daily (via gastric gavage; 4 weeks) with 0.9% saline (control), BaP (75 mg/kg body weight (b.w.)), SDG (100 mg/kg b.w.), SDG (100 mg/kg b.w.)+BaP (75 mg/kg b.w.). Results showed that the mice treated with SDG + BaP had significantly (P < 0.05) higher body weight, lower organ-to-body weight ratio, alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP) activities, and less levels of serum creatinine (CRE) and blood urea nitrogen (BUN) than those treated with BaP alone. SDG administration alleviated BaP-induced oxidative damages, inflammation and apoptosis. Furthermore, it significantly (P < 0.05) downregulated phosphor-p38 (p-p38) and phosphor-extracellular regulated protein kinases (p-ERK) levels, upregulated mitogen-activated protein kinase phosphatase-1 (MKP-1) level, and suppressed miR-101a expression compared with BaP alone group. Taken together, these results showed for the first time that SDG has protective effects against BaP-induced liver and kidney toxicity in mice through regulating oxidative stress, inflammation and apoptosis via miR-101a/MKP-1-mediated p38 and ERK pathway.
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Injúria Renal Aguda/metabolismo , Benzo(a)pireno/toxicidade , Butileno Glicóis/farmacologia , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Glucosídeos/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Animais , Fosfatase 1 de Especificidade Dupla/genética , Fosfatase 1 de Especificidade Dupla/metabolismo , Masculino , Camundongos , MicroRNAs/genética , MicroRNAs/metabolismoRESUMO
Copper is an essential nutrient whose redox properties make it both beneficial and toxic to the cell. Recent progress in studying transition metal signalling has forged new links between researchers of different disciplines that can help translate basic research in the chemistry and biology of copper into clinical therapies and diagnostics to exploit copper-dependent disease vulnerabilities. This concept is particularly relevant in cancer, as tumour growth and metastasis have a heightened requirement for this metal nutrient. Indeed, the traditional view of copper as solely an active site metabolic cofactor has been challenged by emerging evidence that copper is also a dynamic signalling metal and metalloallosteric regulator, such as for copper-dependent phosphodiesterase 3B (PDE3B) in lipolysis, mitogen-activated protein kinase kinase 1 (MEK1) and MEK2 in cell growth and proliferation and the kinases ULK1 and ULK2 in autophagy. In this Perspective, we summarize our current understanding of the connection between copper and cancer and explore how challenges in the field could be addressed by using the framework of cuproplasia, which is defined as regulated copper-dependent cell proliferation and is a representative example of a broad range of metalloplasias. Cuproplasia is linked to a diverse array of cellular processes, including mitochondrial respiration, antioxidant defence, redox signalling, kinase signalling, autophagy and protein quality control. Identifying and characterizing new modes of copper-dependent signalling offers translational opportunities that leverage disease vulnerabilities to this metal nutrient.
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Cobre , Neoplasias , Autofagia , Proliferação de Células , Cobre/metabolismo , Humanos , Transdução de SinaisRESUMO
In-depth insights in cancer biology over the past decades have highlighted the important roles of epigenetic mechanisms in the initiation and progression of tumorigenesis. The cancer epigenome usually experiences multiple alternations, including genome-wide DNA hypomethylation and site-specific DNA hypermethylation, various histone posttranslational modifications, and dysregulation of non-coding RNAs (ncRNAs). These epigenetic changes are plastic and reversible, and could potentially occur in the early stage of carcinogenesis preceding genetic mutation, offering unique opportunities for intervention therapies. Therefore, targeting the cancer epigenome or cancer epigenetic dysregulation with some selected agents (called epi-drugs) represents an evolving and promising strategy for cancer chemoprevention and therapy. Phytochemicals, as a class of pleiotropic molecules, have manifested great potential in modulating different cancer processes through epigenetic machinery, of which green tea polyphenol epigallocatechin-3-gallate (EGCG) is one of the most extensively studied. In this review, we first summarize epigenetic events involved in the pathogenesis of cancer, including DNA/RNA methylations, histone modifications and ncRNAs' dysregulations. We then focus on the recently discovered roles of phytochemicals, with a special emphasis on EGCG, in modulating different cancer processes through regulating epigenetic machinery. We finally discuss limitations of EGCG as an epigenetic modulator for cancer chemoprevention and treatment and offer potential strategies to overcome the shortcomings.
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Neoplasias , Chá , Catequina/análogos & derivados , Epigênese Genética , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/genética , Polifenóis/farmacologia , Polifenóis/uso terapêutico , Chá/químicaRESUMO
Lung cancer is one of the most common cancers in the world. Although medical treatment has made impressive progress in recent years, it is still one of the leading causes of cancer-related deaths in men and women. Ferroptosis is a type of non-apoptotic cell death modality, usually characterized by iron-dependent lipid peroxidation, rather than caspase-induced protein cleavage. Excessive or lack of ferroptosis is associated with a variety of diseases, including cancer and ischaemia-reperfusion injury. Recent preclinical evidence suggests that targeting ferroptotic pathway is a potential strategy for the treatment of lung cancer. In this review, we summarize the core mechanism and regulatory network of ferroptosis in lung cancer cells, and highlight ferroptosis induction-related tumor therapies. The reviewed information may provide new insights for targeted lung cancer therapy.
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Copper (Cu) plays a pivotal role in cancer progression by acting as a co-factor that regulates the activity of many enzymes and structural proteins in cancer cells. Therefore, Cu-based complexes have been investigated as novel anticancer metallodrugs and are considered as a complementary strategy for currently used platinum agents with undesirable general toxicity. Due to the high failure rate and increased cost of new drugs, there is a global drive towards the repositioning of known drugs for cancer treatment in recent years. Disulfiram (DSF) is a first-line antialcoholism drug used in clinics for more than 65 yr. In combination with Cu, it has shown great potential as an anticancer drug by targeting a wide range of cancers. The reaction between DSF and Cu ions forms a copper diethyldithiocarbamate complex (Cu(DDC)2 also known as CuET) which is the active, potent anticancer ingredient through inhibition of NF-κB and ubiquitin-proteasome system as well as alteration of the intracellular reactive oxygen species (ROS). Importantly, DSF/Cu inhibits several molecular targets related to drug resistance, stemness, angiogenesis and metastasis and is thus considered as a novel strategy for overcoming tumour recurrence and relapse in patients. Despite its excellent anticancer efficacy, DSF has proven unsuccessful in several cancer clinical trials. This is likely due to the poor stability, rapid metabolism and/or short plasma half-life of the currently used oral version of DSF and the inability to form Cu(DDC)2 at relevant concentrations in tumour tissues. Here, we summarize the scientific rationale, molecular targets, and mechanisms of action of DSF/Cu in cancer cells and the outcomes of oral DSF ± Cu in cancer clinical trials. We will focus on the novel insights on harnessing the immune system and hypoxic microenvironment using DSF/Cu complex and discuss the emerging delivery strategies that can overcome the shortcomings of DSF-based anticancer therapies and provide opportunities for translation of DSF/Cu or its Cu(DDC)2 complex into cancer therapeutics.
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Activated leukocyte cell adhesion molecule (ALCAM), also known as CD166, is a cell adhesion protein that is found in multiple cell types. ALCAM has multiple and diverse roles in various physiological and pathological conditions, including inflammation and cancer. There has been compelling evidence of ALCAM's prognostic value in solid cancers, indicating that it is a potential therapeutic target. The present article overviews the recent findings and progress in ALCAM and its involvement in cancer, with a primary focus on its clinical connections in cancer and therapeutic values.
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Deubiquitinates (DUBs) have been suggested as novel promising targets for cancer therapies. Accumulating experimental evidence suggests that some metal compounds have the potential to induce cancer cell death via inhibition of DUBs. We previously reported that auranofin, a gold(I)-containing agent used for the treatment of rheumatoid arthritis in clinics, can induce cell death by inhibiting proteasomal DUBs in a series of cancer cell lines. Unfortunately, currently available gold compounds are not potent in inhibiting DUBs. Here, we report that: (i) aumdubin, a synthetic derivative of auranofin, exhibited stronger DUB-inhibiting and apoptosis-inducing activities than auranofin in lung cancer cells; (ii) aumdubin shows high affinity for mitochondrial DUB USP30; (iii) aumdubin induces apoptosis by increasing the ubiquitination and mitochondrial location of Bax protein; and (iv) USP30 inhibition may contribute to Bax-dependent apoptosis induced by aumdubin in lung cancer cells. These results suggest that gold(I)-containing agent aumdubin induces Bax-dependent apoptosis partly through inhibiting the mitochondrial DUB USP30, which could open new avenues for lung cancer therapy.
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BACKGROUND: Over recent years, there has been an increasing focus on the repurposing of existing, well-known medications for new, novel usage. One such drug is metformin, typically utilized in the management of diabetes, which demonstrates a positive relationship between its administration and lower cancer morbidity and mortality. Based on this finding, numerous studies and clinical trials have been conducted to examine the potential usage of metformin as an anticancer agent. OBJECTIVE: This article aims to summarize metformin's anticancer effects through reviewing its literatures and patents, with a focus on its potential to be repurposed for cancer therapy. METHODS: Various databases were examined using keywords, 'Metformin' and 'Cancer'. Research articles were collected through the PubMed database, clinical trials were obtained from the Clinical Trials database, and patents were collected through the Google Patents database. RESULTS: Metformin shows antineoplastic activity in various models. These anticancer properties appear to synergize with existing chemotherapeutics, which allows a reduction in drug dosage without losing potency while minimizing adverse effects. Numerous patents on metformin have been filed which claim various combination therapies, delivery methods, and uses for cancer therapy, displaying an increasing interest in metformin's anticancer potential. CONCLUSION: Preclinical studies, along with early phase clinical trials, have examined the antitumor properties of metformin on a variety of cancers. Metformin's anticancer effects are well documented, demonstrating a great promise in improving current cancer therapies. However, there is a significant lack of late phase clinical trials, specifically those involving nondiabetic cancer patients, and therefore further research in this area is required.
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Antineoplásicos/farmacologia , Metformina/farmacologia , Neoplasias/tratamento farmacológico , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Reposicionamento de Medicamentos , Sinergismo Farmacológico , Humanos , Hipoglicemiantes/farmacologia , Metformina/administração & dosagem , Metformina/efeitos adversos , Patentes como AssuntoRESUMO
Characterizing mechanisms of protein homeostasis, a process of balancing between protein synthesis and protein degradation, is important for understanding the potential causes of human diseases. The ubiquitin-proteasome system (UPS) is a well-studied mechanism of protein catabolism, which is responsible for eliminating misfolded, damaged, or aging proteins, thereby maintaining quality and quantity of cellular proteins. The UPS is composed of multiple components, including a series of enzymes (E1, E2, E3, and deubiquitinase [DUB]) and 26S proteasome (19S regulatory particles + 20S core particle). An impaired UPS pathway is involved in multiple diseases, including cancer. Several proteasome inhibitors, such as bortezomib, carfilzomib, and ixazomib, are approved to treat patients with certain cancers. However, their applications are limited by side effects, drug resistance, and drug-drug interactions observed in their clinical processes. To overcome these shortcomings, alternative UPS inhibitors have been searched for in many fields. Copper complexes (e.g., CuET, CuHQ, CuCQ, CuPDTC, CuPT, and CuHK) are found to be able to inhibit a core component of the UPS machinery, such as 20S proteasome, 19S DUBs, and NPLOC4/NPL4 complex, and are proposed to be one class of metal-based anticancer drugs. In this review, we will summarize functions and applications of copper complexes in a concise perspective, with a focus on connections between the UPS and cancer.
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Nobiletin, a polymethoxyflavone widely present in the peel of citrus fruits, has significant anti-inflammatory activity. Autophagy plays a critical role in maintaining cell homeostasis by promoting the degradation of intracellular structures in response to various stress. Recent research suggests the involvement of autophagy in the inflammatory process and therefore some inflammation-related diseases. However, the "cross-talk" between autophagy and nobiletin's anti-inflammation response remains not well elucidated. Therefore, this study was initiated with the aim of investigating the role of autophagy in nobiletin's protective effect against inflammation in lipopolysaccharide (LPS)-stimulated RAW264.7 cells. Results showed that nobiletin significantly (P < 0.05) inhibited the release of nitric oxide (NO) and decreased the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in a dose-dependent manner. Moreover, nobiletin significantly (P < 0.05) promoted autophagy as evidenced by the appearance of more autophagosomes, up-regulated LC3II protein, low-regulated p62 protein, and increased autophagy-related (Atg) genes' expression compared with the control treated with LPS alone. Addition of chloroquine, an autophagy inhibitor, alleviated nobiletin's anti-inflammatory effect, further supporting the requirement of an active autophagy process for the citrus peel flavonoid's biological activity. Mechanistically, we found that nobiletin treatment leads to activation of the IL-6/STAT3/FOXO3a signal pathway through the down-regulation of IL-6 and STAT3 phosphorylation and the upregulation of FOXO3a phosphorylation in the cell nucleus, which is responsible for induction of macrophage autophagy. Taken together, our study provides evidence that nobiletin suppresses inflammatory response through enhancing autophagy through activating the IL-6/STAT3/FOXO3a pathway in macrophage cells.
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Flavonas/farmacologia , Proteína Forkhead Box O3/metabolismo , Inflamação/induzido quimicamente , Interleucina-6/metabolismo , Lipopolissacarídeos/toxicidade , Fator de Transcrição STAT3/metabolismo , Animais , Antioxidantes/química , Antioxidantes/farmacologia , Autofagia , Citrus , Flavonas/química , Proteína Forkhead Box O3/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Inflamação/tratamento farmacológico , Interleucina-6/genética , Camundongos , Células RAW 264.7 , Fator de Transcrição STAT3/genéticaRESUMO
The ubiquitin-proteasome system (UPS) plays a central role in the degradation of cellular proteins. Targeting protein degradation has been validated as an effective strategy for cancer therapy since 2003. Several components of the UPS have been validated as potential anticancer targets, including 20S proteasomes, 19S proteasome-associated deubiquitinases (DUBs) and ubiquitin ligases (E3s). 20S proteasome inhibitors (such as bortezomib/BTZ and carfilzomib/CFZ) have been approved by the U.S. Food and Drug Administration (FDA) for the treatment of multiple myeloma (MM) and some other liquid tumors. Although survival of MM patients has been improved by the introduction of BTZ-based therapies, these clinical 20S proteasome inhibitors have several limitations, including emergence of resistance in MM patients, neuro-toxicities, and little efficacy in solid tumors. One of strategies to improve the current status of cancer treatment is to repurpose old drugs with UPS-inhibitory properties as new anticancer agents. Old drug reposition represents an attractive drug discovery approach compared to the traditional de novo drug discovery process which is time-consuming and costly. In this review, we summarize status of repurposed inhibitors of various UPS components, including 20S proteasomes, 19S-associated DUBs, and ubiquitin ligase E3s. The original and new mechanisms of action, molecular targets, and potential anticancer activities of these repurposed UPS inhibitors are reviewed, and their new uses including combinational therapies for cancer treatment are discussed.
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Antineoplásicos/uso terapêutico , Descoberta de Drogas , Reposicionamento de Medicamentos/métodos , Terapia de Alvo Molecular , Neoplasias/tratamento farmacológico , Complexo de Endopeptidases do Proteassoma/química , Inibidores de Proteassoma/uso terapêutico , Animais , Humanos , Ubiquitina/metabolismoRESUMO
The ubiquitin-proteasome system (UPS) plays an important role in maintaining protein homeostasis by degrading intracellular proteins. In the proteasome, poly-ubiquitinated proteins are deubiquitinated by three deubiquitinases (DUBs) associated with 19S regulatory particle before degradation via 20S core particle. Ubiquitin carboxyl-terminal hydrolase L5 (UCHL5) is one of three proteasome-associated DUBs that control the fate of ubiquitinated substrates implicated in cancer survival and progression. In this study, we have performed virtual screening of an FDA approved drug library with UCHL5 and discovered tiaprofenic acid (TA) as a potential binder. With molecular docking analysis and in-vitro DUB assay, we have designed, synthesized, and evaluated a series of TA derivatives for inhibition of UCHL5 activity. We demonstrate that one TA derivative, TAB2, acts as an inhibitor of UCHL5.