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1.
BMC Nephrol ; 25(1): 124, 2024 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-38589827

RESUMO

BACKGROUND: Kidney transplant recipients (KTRs) are at risk of severe coronavirus disease 2019 (COVID-19), and even now that Omicron subvariants have become dominant, cases of severe disease are certain to occur. The aims of this retrospective study were to evaluate the efficacy of antiviral treatment for COVID-19 and to identify risk factors for severe disease in KTRs during Omicron subvariant-dominant periods. METHODS: A total of 65 KTRs diagnosed with COVID-19 who received antiviral treatment between July 2022 and September 2023 were analyzed. Mild cases received oral molnupiravir (MP) as outpatient therapy, while moderate or worse cases received intravenous remdesivir (RDV) as inpatient therapy. In principle, mycophenolate mofetil was withdrawn and switched to everolimus. We investigated the efficacy of antiviral treatment and compared the clinical parameters of mild/moderate and severe/critical cases to identify risk factors for severe COVID-19. RESULTS: Among 65 cases, 49 were mild, 6 were moderate, 9 were severe, and 1 was of critical severity. MP was administered to 57 cases; 49 (86%) improved and 8 (14%) progressed. RDV was administered to 16 cases; 14 (87%) improved and 2 (13%) progressed. Seventeen (26%) cases required hospitalization, and none died. Comparisons of the severe/critical group (n = 10) with the mild/moderate group (n = 55) demonstrated that the severe/critical group had a significantly higher median age (64 vs. 53 years, respectively; p = 0.0252), prevalence of diabetes (70% vs. 22%, respectively; p = 0.0047) and overweight/obesity (40% vs. 11%, respectively; p = 0.0393), as well as a significantly longer median time from symptom onset to initial antiviral therapy (3 days vs. 1 day, respectively; p = 0.0026). Multivariate analysis showed that a longer time from symptom onset to initial antiviral treatment was an independent risk factor for severe COVID-19 (p = 0.0196, odds ratio 1.625, 95% confidence interval 1.081-2.441). CONCLUSION: These findings suggest that a longer time from symptom onset to initial antiviral treatment is associated with a higher risk of severe COVID-19 in KTRs. Initiating antiviral treatment as early as possible is crucial for preventing severe outcomes; this represents a valuable insight into COVID-19 management in KTRs.


Assuntos
COVID-19 , Citidina/análogos & derivados , Hidroxilaminas , Transplante de Rim , Humanos , Estudos Retrospectivos , Resultado do Tratamento , Fatores de Risco , Antivirais/uso terapêutico , Transplantados
2.
PLoS One ; 18(10): e0287059, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37819994

RESUMO

The development of diabetes mellitus (DM) after living donor kidney transplantation (KT) is a risk factor for worsening transplant kidney function, cardiac disease, and cerebrovascular disease, which may affect prognosis after KT. At our institution, all patients' glucose tolerance is evaluated perioperatively by oral glucose tolerance tests (OGTTs) at pre-KT, and 3, 6, and 12 month (mo.) after KT. We analyzed the insulinogenic index (ISI) and homeostasis model assessment beta cell (HOMA-ß) based on the immunoreactive insulin (IRI) levels to determine how glucose tolerance changed after KT in 214 patients who had not been diagnosed with DM before KT. In addition, we analyzed the body mass index (BMI) which may also influence glucose tolerance after KT. The concentration of tacrolimus (TAC) in blood was also measured as the area under the curve (AUC) to examine its effects at each sampling point. The preoperative-OGTTs showed that DM was newly diagnosed in 22 of 214 patients (10.3%) who had not been given a diagnosis of DM by the pre-KT fasting blood sugar (FBS) tests. The glucose tolerance was improved in 15 of 22 DM patients at 12 mo. after KT. ISI and IRI deteriorated only at 3 mo. after KT but improved over time. There was a trend of an inverse correlation between HOMA-ß and TAC-AUC. We also found inverse correlations between IRI and an increase in BMI from 3 to 12 mo. after KT. Early corticosteroid withdrawal or the steroid minimization protocol with tacrolimus to maintain a low level of diabetogenic tacrolimus and BMI decrease after KT used by our hospital individualizes lifestyle interventions for each patient might contribute to an improvement in post-KT glucose tolerance.


Assuntos
Diabetes Mellitus Tipo 2 , Resistência à Insulina , Transplante de Rim , Humanos , Tacrolimo , Insulina , Transplante de Rim/efeitos adversos , População do Leste Asiático , Diabetes Mellitus Tipo 2/etiologia , Glucose , Esteroides , Peso Corporal , Glicemia
3.
FEBS Open Bio ; 13(6): 1056-1066, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-37079001

RESUMO

Combination chemotherapy with gemcitabine and cisplatin (GC) is recommended as the primary treatment for advanced bladder cancer (BC). However, the benefits of this approach are limited owing to the acquisition of drug resistance. Here, we found that gemcitabine-resistant and cisplatin-resistant BCs do not exhibit cross-resistance, and that these BCs exhibit different mRNA patterns, as revealed using RNA sequence analysis. To overcome drug resistance, we used the newly developed pan-RAS inhibitor Compound 3144. Compound 3144 inhibited cell viability through suppression of RAS-dependent signaling in gemcitabine- and cisplatin-resistant BCs. RNA sequencing revealed that several genes and pathways, particularly those related to the cell cycle, were significantly downregulated in Compound 3144-treated BCs. These findings provide insights into potential therapeutic strategies for treating BC.


Assuntos
Antineoplásicos , Neoplasias da Bexiga Urinária , Humanos , Gencitabina , Cisplatino , Resistencia a Medicamentos Antineoplásicos/genética , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/genética , Desoxicitidina/farmacologia , Desoxicitidina/uso terapêutico
4.
Biochem Biophys Res Commun ; 611: 99-106, 2022 06 30.
Artigo em Inglês | MEDLINE | ID: mdl-35487063

RESUMO

In recent years, cancer metabolism has attracted attention as a therapeutic target, and glutamine metabolism is considered one of the most important metabolic processes in cancer. Solute carrier family 1 member 5 (SLC1A5) is a sodium channel that functions as a glutamine transporter. In various cancer types, SLC1A5 gene expression is enhanced, and cancer cell growth is suppressed by inhibition of SLC1A5. However, the involvement of SLC1A5 in clear cell renal cell carcinoma (ccRCC) is unclear. Therefore, in this study, we evaluated the clinical importance of SLC1A5 in ccRCC using The Cancer Genome Atlas database. Our findings confirmed that SLC1A5 was a prognosis factor for poor survival in ccRCC. Furthermore, loss-of-function assays using small interfering RNAs or an SLC1A5 inhibitor (V9302) in human ccRCC cell lines (A498 and Caki1) showed that inhibition of SLC1A5 significantly suppressed tumor growth, invasion, and migration. Additionally, inhibition of SLC1A5 by V9302 in vivo significantly suppressed tumor growth, and the antitumor effects of SLC1A5 inhibition were related to cellular senescence. Our findings may improve our understanding of ccRCC and the development of new treatment strategies for ccRCC.


Assuntos
Sistema ASC de Transporte de Aminoácidos , Carcinoma de Células Renais , Senescência Celular , Neoplasias Renais , Antígenos de Histocompatibilidade Menor , Sistema ASC de Transporte de Aminoácidos/genética , Sistema ASC de Transporte de Aminoácidos/metabolismo , Carcinoma de Células Renais/genética , Linhagem Celular Tumoral , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Glutamina/metabolismo , Humanos , Neoplasias Renais/genética , Antígenos de Histocompatibilidade Menor/genética , RNA Interferente Pequeno/genética
5.
Mol Oncol ; 16(6): 1329-1346, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35148461

RESUMO

Patients with advanced bladder cancer are generally treated with a combination of chemotherapeutics, including gemcitabine, but the effect is limited due to acquisition of drug resistance. Thus, in this study, we investigated the mechanism of gemcitabine resistance. First, gemcitabine-resistant cells were established and resistance confirmed in vitro and in vivo. Small RNA sequencing analyses were performed to search for miRNAs involved in gemcitabine resistance. miR-99a-5p, selected as a candidate miRNA, was downregulated compared to its parental cells. In gain-of-function studies, miR-99a-5p inhibited cell viabilities and restored sensitivity to gemcitabine. RNA sequencing analysis was performed to find the target gene of miR-99a-5p. SMARCD1 was selected as a candidate gene. Dual-luciferase reporter assays showed that miR-99a-5p directly regulated SMARCD1. Loss-of-function studies conducted with si-RNAs revealed suppression of cell functions and restoration of gemcitabine sensitivity. miR-99a-5p overexpression and SMARCD1 knockdown also suppressed gemcitabine-resistant cells in vivo. Furthermore, ß-galactosidase staining showed that miR-99a-5p induction and SMARCD1 suppression contributed to cellular senescence. In summary, tumor-suppressive miR-99a-5p induced cellular senescence in gemcitabine-resistant bladder cancer cells by targeting SMARCD1.


Assuntos
MicroRNAs , Neoplasias da Bexiga Urinária , Linhagem Celular Tumoral , Proliferação de Células , Senescência Celular/genética , Proteínas Cromossômicas não Histona/genética , Desoxicitidina/análogos & derivados , Regulação Neoplásica da Expressão Gênica , Humanos , MicroRNAs/genética , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/genética , Gencitabina
7.
BMC Cancer ; 21(1): 48, 2021 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-33430801

RESUMO

BACKGROUND: Cisplatin-based chemotherapy is recommended as the primary treatment for advanced bladder cancer (BC) with unresectable or metastatic disease. However, the benefits are limited due to the acquisition of drug resistance. The mechanisms of resistance remain unclear. Although there are some reports that some molecules are associated with cisplatin resistance in advanced BC, those reports have not been fully investigated. Therefore, we undertook a new search for cisplatin resistance-related genes targeted by tumor suppressive microRNAs as well as genes that were downregulated in cisplatin-resistant BC cells and clinical BC tissues. METHODS: First, we established cisplatin-resistant BOY and T24 BC cell lines (CDDP-R-BOY, CDDP-R-T24). Then, Next Generation Sequence analysis was performed with parental and cisplatin-resistant cell lines to search for the microRNAs responsible for cisplatin resistance. We conducted gain-of-function analysis of microRNAs and their effects on cisplatin resistance, and we searched target genes comprehensively using Next Generation mRNA sequences. RESULTS: A total of 28 microRNAs were significantly downregulated in both CDDP-R-BOY and CDDP-R-T24. Among them, miR-486-5p, a tumor suppressor miRNA, was negatively correlated with the TNM classification of clinical BC samples in The Cancer Genome Atlas (TCGA) database. Transfection of miRNA-486-5p significantly inhibited cancer cell proliferation, migration, and invasion, and also improved the cells' resistance to cisplatin. Among the genes targeted by miRNA-486-5p, we focused on enoyl-CoA, hydratase/3-hydroxyacyl CoA dehydrogenase (EHHADH), which is involved in the degradation of fatty acids. EHHADH was directly regulated by miRNA-486-5p as determined by a dual-luciferase reporter assay. Loss-of-function study using EHHADH si-RNA showed significant inhibitions of cell proliferation, migration, invasion and the recovery of cisplatin sensitivity. CONCLUSION: Identification of EHHADH as a target of miRNA-486-5p provides novel insights into the potential mechanisms of cisplatin resistance in BC.


Assuntos
Biomarcadores Tumorais/metabolismo , Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos , Regulação Neoplásica da Expressão Gênica , MicroRNAs/genética , Enzima Bifuncional do Peroxissomo/metabolismo , Neoplasias da Bexiga Urinária/patologia , Animais , Antineoplásicos/farmacologia , Apoptose , Biomarcadores Tumorais/genética , Movimento Celular , Proliferação de Células , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Enzima Bifuncional do Peroxissomo/genética , Células Tumorais Cultivadas , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
8.
PLoS One ; 15(7): e0236119, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32667929

RESUMO

The alcohol-abuse drug disulfiram has antitumor effects against diverse cancer types via inhibition of the ubiquitin-proteasome protein nuclear protein localization protein 4 (NPL4). However, the antitumor effects of NPL4 and disulfiram in clear cell renal cell carcinoma (ccRCC) are unclear. Here, we evaluated the therapeutic potential of targeting the ubiquitin-proteasome pathway using disulfiram and RNA interference and investigated the mechanisms underlying disulfiram in ccRCC. According to data from The Cancer Genome Atlas, NPL4 mRNA expression was significantly upregulated in clinical ccRCC samples compared with that in normal kidney samples, and patients with high NPL4 expression had poor overall survival compared with patients with low NPL4 expression. Disulfiram and NPL4 siRNA inhibited ccRCC cell proliferation in vitro, and disulfiram inhibited ccRCC tumor growth in a xenograft model. Synergistic antiproliferative effects were observed for combination treatment with disulfiram and sunitinib in vitro and in vivo. In RCC cells from mice treated with disulfiram and/or sunitinib, several genes associated with serine biosynthesis and aldose reductase were downregulated in cells treated with disulfiram or sunitinib alone and further downregulated in cells treated with both disulfiram and sunitinib. These findings provided insights into the mechanisms of disulfiram and suggested novel therapeutic strategies for RCC treatment.


Assuntos
Carcinoma de Células Renais/tratamento farmacológico , Dissulfiram/farmacologia , Reposicionamento de Medicamentos/métodos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias Renais/tratamento farmacológico , Proteínas Nucleares/antagonistas & inibidores , Inibidores de Acetaldeído Desidrogenases/farmacologia , Animais , Apoptose , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Carcinoma de Células Renais/metabolismo , Carcinoma de Células Renais/patologia , Proliferação de Células , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Renais/metabolismo , Neoplasias Renais/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Prognóstico , RNA Interferente Pequeno/genética , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
9.
Mol Oncol ; 14(9): 2190-2202, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32386122

RESUMO

d-3-Phosphoglycerate dehydrogenase (PHGDH) conducts an important step in the synthesis of serine. Importantly, the PHGDH gene is often amplified in certain cancers. Our previous studies revealed that PHGDH gene amplification was associated with poor overall survival in clear cell renal cell carcinoma (ccRCC) and that metabolic reprogramming of serine synthesis through PHGDH recruitment allowed ccRCC cells to survive in unfavorable environments. There have been no investigations of the role of PHGDH expression in bladder cancer (BC). In this investigation, we examined the clinical importance of PHDGH in BC. Furthermore, we asked whether PHGDH expression could be exploited for BC therapy. Finally, we investigated the regulatory mechanisms that modulated the expression of PHGDH. Using data from The Cancer Genome Atlas, we found that patients with high-grade BC had significantly higher PHGDH expression levels than did those with low-grade BC. In addition, patients with high PHGDH expression did not survive as long as those with low expression. PHGDH downregulation by si-RNAs or an inhibitor in BC cell lines significantly inhibited proliferative ability and induced apoptosis. Furthermore, combined treatment using a PHGDH inhibitor and gemcitabine/cisplatin achieved synergistic tumor suppression compared to use of a single agent both in vitro as well as in vivo. Mechanistic analyses of PHGDH regulation showed that PHGDH expression might be associated with DNA copy number and hypomethylation in BC. These findings suggest novel therapeutic strategies could be used in BC. Finally, our data enhance our understanding of the role of PHGDH in BC.


Assuntos
Cisplatino/uso terapêutico , Metilação de DNA/genética , Desoxicitidina/análogos & derivados , Regulação Neoplásica da Expressão Gênica , Terapia de Alvo Molecular , Fosfoglicerato Desidrogenase/genética , Regiões Promotoras Genéticas/genética , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/genética , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Cisplatino/farmacologia , Desoxicitidina/farmacologia , Desoxicitidina/uso terapêutico , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/genética , Feminino , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Camundongos Endogâmicos BALB C , Camundongos Nus , Fosfoglicerato Desidrogenase/antagonistas & inibidores , Fosfoglicerato Desidrogenase/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Neoplasias da Bexiga Urinária/enzimologia , Gencitabina
10.
PLoS One ; 15(5): e0232545, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32379831

RESUMO

Exosomes are 40-100 nm nano-sized extracellular vesicles. They are released from many cell types and move into the extracellular space, thereby transferring their components to recipient cells. Exosomes are receiving increasing attention as novel structures participating in intracellular communication. RAB27B is one of the leading proteins involved in exosome secretion, and oncogenic effects have been reported in several cancers. In recent years, molecularly targeted agents typified by sunitinib are widely used for the treatment of metastatic or recurrent renal cell carcinoma (RCC). However, intrinsic or acquired resistance to sunitinib has become a major issue. The present study aimed to elucidate the role of RAB27B in RCC including sunitinib-resistant and its role in exosomes. Bioinformatic analyses revealed that high expression of RAB27B correlates with progression of RCC. The expression of RAB27B protein in RCC cell lines was significantly enhanced compared with that in normal kidney cell lines. Furthermore, RAB27B protein expression was enhanced in all of the tested sunitinib-resistant RCC cell lines compared to parental cells. Although no specific effect of RAB27B on exosomes was identified in RCC cells, loss-of-function studies demonstrated that knockdown of RAB27B suppressed cell proliferation, migration and invasive activities. Moreover, anti-tumor effects of RAB27B downregulation were also observed in sunitinib-resistant RCC cells. RNA sequence and pathway analysis suggested that the oncogenic effects of RAB27B might be associated with MAPK and VEGF signaling pathways. These results showed that RAB27B is a prognostic marker and a novel therapeutic target in sunitinib-sensitive and -resistant RCCs. Further analyses should improve our understanding of sunitinib resistance in RCC.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma de Células Renais/metabolismo , Exossomos/metabolismo , Neoplasias Renais/metabolismo , Sunitinibe/uso terapêutico , Proteínas rab de Ligação ao GTP/metabolismo , Western Blotting , Carcinoma de Células Renais/tratamento farmacológico , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Humanos , Rim/metabolismo , Neoplasias Renais/tratamento farmacológico
11.
Cancer Sci ; 111(5): 1607-1618, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32232883

RESUMO

Sunitinib, a multitargeted receptor tyrosine kinase inhibitor including vascular endothelial growth factor, has been widely used as a first-line treatment against metastatic renal cell carcinoma (mRCC). However, mRCC often acquires resistance to sunitinib, rendering it difficult to treat with this agent. Recently, Rapalink-1, a drug that links rapamycin and the mTOR kinase inhibitor MLN0128, has been developed with excellent therapeutic effects against breast cancer cells carrying mTOR resistance mutations. The aim of the present study was to evaluate the in vitro and in vivo therapeutic efficacy of Rapalink-1 against renal cell carcinoma (RCC) compared to temsirolimus, which is commonly used as a small molecule inhibitor of mTOR and is a derivative of rapamycin. In comparison with temsirolimus, Rapalink-1 showed significantly greater effects against proliferation, migration, invasion and cFolony formation in sunitinib-naïve RCC cells. Inhibition was achieved through suppression of the phosphorylation of substrates in the mTOR signal pathway, such as p70S6K, eukaryotic translation initiation factor 4E-binding protein 1 (4EBP1) and AKT. In addition, Rapalink-1 had greater tumor suppressive effects than temsirolimus against the sunitinib-resistant 786-o cell line (SU-R 786-o), which we had previously established, as well as 3 additional SU-R cell lines established here. RNA sequencing showed that Rapalink-1 suppressed not only the mTOR signaling pathway but also a part of the MAPK signaling pathway, the ErbB signaling pathway and ABC transporters that were associated with resistance to several drugs. Our study suggests the possibility of a new treatment option for patients with RCC that is either sunitinib-sensitive or sunitinib-resistant.


Assuntos
Carcinoma de Células Renais/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias Renais/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Sirolimo/análogos & derivados , Sunitinibe/farmacologia , Serina-Treonina Quinases TOR/antagonistas & inibidores , Animais , Apoptose/efeitos dos fármacos , Carcinoma de Células Renais/metabolismo , Carcinoma de Células Renais/patologia , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Feminino , Humanos , Neoplasias Renais/metabolismo , Neoplasias Renais/patologia , Camundongos , Camundongos Nus , Inibidores de Proteínas Quinases/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Sirolimo/farmacologia , Sirolimo/uso terapêutico , Sunitinibe/uso terapêutico , Serina-Treonina Quinases TOR/metabolismo
13.
Int J Oncol ; 54(5): 1759-1770, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30816432

RESUMO

Sunitinib is the most common primary molecular­targeted agent for metastatic clear cell renal cell carcinoma (ccRCC); however, intrinsic or acquired sunitinib resistance has become a significant problem in medical practice. The present study focused on microRNA (miR)­99a­3p, which was significantly downregulated in clinical sunitinib­resistant ccRCC tissues in previous screening analyses, and investigated the molecular network associated with it. The expression levels of miR­99a­3p and its candidate target genes were evaluated in RCC cells, including previously established sunitinib­resistant 786­o (SU­R­786­o) cells, and clinical ccRCC tissues, using reverse transcription­quantitative polymerase chain reaction. Gain­of­function studies demonstrated that miR­99a­3p significantly suppressed cell proliferation and colony formation in RCC cells, including the SU­R­786­o cells, by inducing apoptosis. Based on in silico analyses and RNA sequencing data, followed by luciferase reporter assays, ribonucleotide reductase regulatory subunit­M2 (RRM2) was identified as a direct target of miR­99a­3p in the SU­R­786­o cells. Loss­of­function studies using small interfering RNA against RRM2 revealed that cell proliferation and colony growth were significantly inhibited via induction of apoptosis, particularly in the SU­R­786­o cells. Furthermore, the RRM2 inhibitor Didox (3,4­dihydroxybenzohydroxamic acid) exhibited anticancer effects in the SU­R­786­o cells and other RCC cells. To the best of our knowledge, this is the first report demonstrating that miR­99a­3p directly regulates RRM2. Identifying novel genes targeted by tumor­suppressive miR­99a­3p in sunitinib­resistant RCC cells may improve our understanding of intrinsic or acquired resistance and facilitate the development of novel therapeutic strategies.


Assuntos
Carcinoma de Células Renais/genética , Resistencia a Medicamentos Antineoplásicos , Neoplasias Renais/genética , MicroRNAs/genética , Ribonucleosídeo Difosfato Redutase/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Ácidos Hidroxâmicos/farmacologia , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/metabolismo , Masculino , Pessoa de Meia-Idade , Ribonucleosídeo Difosfato Redutase/metabolismo , Sunitinibe/farmacologia
14.
Int J Oncol ; 53(2): 725-736, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29901113

RESUMO

The active form of the small GTPase RAS binds to downstream effectors to promote cell growth and proliferation. RAS signal enhancement contributes to tumorigenesis, invasion, and metastasis in various different cancers. HRAS proto-oncogene GTPase (HRAS), one of the RAS isoforms, was the first human oncogene for which mutations were reported in T24 bladder cancer (BC) cells in 1982, and HRAS mutation or upregulation has been reported in several cancers. According to data from The Cancer Genome Atlas, HRAS expression was significantly upregulated in clinical BC samples compared to healthy samples (P=0.0024). HRAS expression was also significantly upregulated in BC with HRAS mutation compared to patients without HRAS mutation (P<0.0001). The tumor suppressive effect of salirasib, a RAS inhibitor, has been reported in several cancer types, but only at relatively high concentrations. As such, RAS inhibitors have not been used for clinical applications. The aim of the current study was to investigate the therapeutic potential of targeting HRAS using salirasib and small interfering RNA (siRNA) and to characterize the mechanism by which HRAS functions using recently developed quantitative in vitro proteome-assisted multiple reaction monitoring for protein absolute quantification (iMPAQT), in BC cells. iMPAQT allows measurement of the absolute abundance of any human protein with the high quantitative accuracy. Salirasib and siRNA targeting of HRAS inhibited cell proliferation, migration and invasion in HRAS wild type and HRAS-mutated cell lines. Proteomic analyses revealed that several metabolic pathways, including the oxidative phosphorylation pathway and glycolysis, were significantly downregulated in salirasib-treated BC cells. However, the expression levels of hexokinase 2, phosphoglycerate kinase 1, pyruvate kinase, muscle (PKM)1, PKM2 and lactate dehydrogenase A, which are downstream of RAS and target genes of hypoxia inducible factor-1α, were not notably downregulated, which may explain the high concentration of salirasib required to inhibit cell viability. These findings provide insight into the mechanisms of salirasib, and suggest the need for novel therapeutic strategies to treat cancers such as BC.


Assuntos
Antineoplásicos/administração & dosagem , Farneseno Álcool/análogos & derivados , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Salicilatos/administração & dosagem , Regulação para Cima/efeitos dos fármacos , Neoplasias da Bexiga Urinária/tratamento farmacológico , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Farneseno Álcool/administração & dosagem , Farneseno Álcool/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Redes Reguladoras de Genes , Glicólise/efeitos dos fármacos , Humanos , Camundongos , Mutação , Fosforilação Oxidativa/efeitos dos fármacos , Proteômica , Proto-Oncogene Mas , Salicilatos/farmacologia , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
15.
Oncotarget ; 9(33): 23003-23017, 2018 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-29796168

RESUMO

Sunitinib is a standard molecular-targeted drug used as a first-line treatment for metastatic clear cell renal cell carcinoma (ccRCC); however, resistance to sunitinib has become a major problem in medical practice. Recently, bromodomain containing 4 (BRD4), a member of the bromodomain family proteins, was identified as a promising therapeutic target, and its inhibitor JQ1 has been shown to have inhibitory effects in various human cancers. However, the anti-cancer effects of JQ1 in ccRCC, particularly sunitinib-resistant ccRCC, are still unclear. Here, we aimed to elucidate the anti-cancer effects of JQ1 and the mechanisms underlying BRD4 inhibition in sunitinib-sensitive and -resistant ccRCCs. Analysis of The Cancer Genome Atlas (TCGA) ccRCC cohort showed that patients with high BRD4 expression had shorter overall survival than those with low expression. JQ1 treatment significantly inhibited tumor growth of sunitinib-sensitive and -resistant ccRCC cells in part through MYC regulation. Based on RNA sequencing analyses of ccRCC cells treated with JQ1 to elucidate the mechanisms other than MYC regulation, we identified several oncogenes that may be potential therapeutic targets or prognostic markers; patients with high expression of SCG5, SPOCD1, RGS19, and ARHGAP22 had poorer overall survival than those with low expression in TCGA ccRCC cohort. Chromatin immunoprecipitation assays revealed that these oncogenes may be promising BRD4 targets, particularly in sunitinib-resistant ccRCC cells. These results identified SCG5, SPOCD1, RGS19, and ARHGAP22 as potential prognostic markers and showed that BRD4 inhibition may have applications as a potential therapeutic approach in sunitinib-sensitive and -resistant ccRCC.

16.
Int J Urol ; 18(7): 533-5, 2011 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-21569110

RESUMO

We describe a case of intraparenchymal renal artery aneurysm in a 58-year-old normotensive man with a history of distal ureterectomy. Imaging studies of the pre-existing right renal mass had been interpreted as being consistent with a simple renal cyst. Three years after ureterectomy, a small parietal nodule with contrast enhancement developed within the cyst. Partial nephrectomy was carried out based on a preoperative diagnosis of cystic kidney cancer. Surprisingly, pathological diagnosis was an aneurysm with a revascularized thrombus. Even though the present case represents an extremely rare clinical manifestation of intraparenchymal renal artery aneurysm, clinicians should be aware that imaging studies cannot distinguish all instances of renal vascular disease.


Assuntos
Aneurisma/diagnóstico , Aneurisma/cirurgia , Carcinoma de Células Renais/diagnóstico , Neoplasias Renais/diagnóstico , Artéria Renal/patologia , Artéria Renal/cirurgia , Cistos/diagnóstico , Diagnóstico Diferencial , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Tomografia Computadorizada por Raios X , Ultrassonografia Doppler
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