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1.
Anticancer Res ; 41(9): 4645-4650, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34475093

RESUMO

BACKGROUND/AIM: Previous reports have indicated that increased expression of Jagged-1 (JAG1) may predict chemotherapy response and poor prognosis for patients with recurrent or metastatic colorectal cancer (CRC). This study aimed to investigate the clinical impact of JAG1 expression level in patients with CRC, including recurrence, especially in those diagnosed with lymph node-positive stage III CRC who underwent complete resection and appropriate adjuvant chemotherapy. PATIENTS AND METHODS: All patients were enrolled through a retrospective chart review, and only those for whom the clinical course and all clinical information were adequately determined according to the inclusion criteria were selected for retrospective review through medical records. Immunohistochemical staining of JAG1 was performed using paraffin-embedded tissue. JAG1 expression was determined by scoring for staining intensity and percentage of positively stained cells; the final JAG1 score was determined as the sum of both scores. RESULTS: Sixteen patients who experienced relapse and 15 without (for over 3 years) were selected. The protein expression level of JAG1 showed a tendency for being lower in the group without recurrence, although not statistically significantly (p=0.083); however, the mean JAG1 expression score was significantly lower in the group without recurrence (1.53 vs. 3.19; p=0.004). The patients were divided into two groups with low and high JAG1 expression. The results showed that high JAG1 expression was significantly associated with recurrence of stage III CRC (p=0.029). CONCLUSION: The expression of JAG1 may be a potential novel biomarker for predicting CRC recurrence.


Assuntos
Neoplasias Colorretais/tratamento farmacológico , Proteína Jagged-1/metabolismo , Recidiva Local de Neoplasia/epidemiologia , Regulação para Cima , Idoso , Biomarcadores Tumorais/metabolismo , Quimioterapia Adjuvante , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/metabolismo , Estadiamento de Neoplasias , Prognóstico , Estudos Retrospectivos , Resultado do Tratamento
2.
World J Clin Cases ; 8(19): 4488-4493, 2020 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-33083408

RESUMO

BACKGROUND: Ovarian undifferentiated carcinomas are significantly rare and have an aggressive clinical course. Surgical resection is the only curative treatment in early-stage ovarian undifferentiated carcinomas that has a favorable prognosis. In case of recurrent and metastatic disease, palliative chemotherapy is the only available treatment. However, the effectiveness of standard chemotherapy regimen is not well-known, specifically in the case of extra-ovarian spread. We report an ovarian undifferentiated carcinoma of recurrent and inoperable advanced stage that was successfully treated with high-dose combination chemotherapy. CASE SUMMARY: A 52-year-old woman presented with a 1-mo history of right lower quadrant and epigastric pain. A computed tomography (CT) scan of the abdomen revealed a multicystic mass with extensive internal necrosis of the right ovary without evidence of metastatic disease. A total hysterectomy with bilateral salpingo-oophorectomy and omentectomy was performed, but the surgery had a positive resection margin. Pathologically, it was diagnosed as ovarian undifferentiated carcinoma with sarcomatoid change. Although adjuvant chemotherapy was planned, it was delayed for 6 wk because of postoperative recovery, and the patient complained of abdominal pain. A CT scan and positron emission tomography-CT revealed a huge mass with multiple nodules in the pelvic cavity and para-aortic lymph node metastasis. Instead of standard therapy such as paclitaxel and platinum, combined chemotherapy with etoposide, ifosfamide, and cisplatin was administered. The patient experienced no recurrence for 5 years. CONCLUSION: This is a case of metastatic ovarian undifferentiated carcinoma with sarcomatoid change that was successfully treated with high-dose combination cytotoxic chemotherapy.

3.
World J Clin Cases ; 8(13): 2833-2840, 2020 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-32742992

RESUMO

BACKGROUND: Pembrolizumab is a highly selective IgG4 kappa isotype monoclonal antibody against the programmed cell death-1 (PD-1) molecule. In the treatment of non-small cell lung cancer (NSCLC), pembrolizumab has demonstrated significant efficacy, significant survival outcomes, long-lasting responses, and a good safety profile compared with cytotoxic chemotherapy. CASE SUMMARY: A 79-year-old Korean male presented with a left side palpable neck mass. An ultrasound-guided core-needle biopsy of the largest neck mass was performed, and squamous cell carcinoma was confirmed based on the histological and immunohistochemical findings. He was diagnosed with squamous cell carcinoma of the lung with multiple lymph nodes and rib metastases (T1N3M1b, Stage IVA) using enhanced chest computed tomography and 18F-fluorodeoxyglucose positron emission/computed tomography. After 4 cycles of gemcitabine and carboplatin, we clinically judged the disease as progressive. Owing to the high PD-1 expression demonstrated by the patient, pembrolizumab was initiated (200 mg every 3 wk). After 3 cycles of pembrolizumab, a complete response was achieved. At the 4th cycle of pembrolizumab, the white blood cell count was markedly elevated. Peripheral blood smear analysis and bone marrow biopsy were performed. The patient was diagnosed with acute myelomonocytic leukemia. CONCLUSION: We present the first report of acute myelomonocytic leukemia during pembrolizumab treatment in an NSCLC patient; the mechanism remains unknown.

4.
Anticancer Res ; 40(4): 1897-1904, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32234878

RESUMO

BACKGROUND/AIM: We investigated the clinical role of the molecular targets, APEX1 and Jagged-1, and the Apex1 - Jagged-1 cascade in gastric cancer cells. MATERIALS AND METHODS: We used 6 human gastric cancer cell lines (SNU-1, SNU-5, SNU-16, NCI-N87, KATO- III and AGS), and demonstrated the chemosensitivity of APEX1 and Jagged-1 through the MTT assay and immunoblotting. Tumor growth was assayed following cisplatin and 5-FU treatment using a xenograft model injected with KATO-III cells. Moreover, gastric tumor samples from 9 patients, divided in 2 groups according to chemotherapy response, were examined by immunocytochemical (IHC) staining, and protein expression levels were scored. RESULTS: Following APEX1 knockdown, the MTT assay revealed that the IC50 of cisplatin and 5-FU in AGS cells was decreased approximately 7% and 15%, respectively, however, their decrease in chemoresistant KATO-III cells was decreased by approximately 21% and 67% for cisplatin and 5-FU, respectively. The tumor volume of KATO-III/sicontrol mice treated with cisplatin and 5-FU was affected less, compared with KATO-III/siAPEX1 mice treated with cisplatin and 5-FU. Also, the expression levels of APEX1, Jagged-1 and CD133, assayed by IHC staining, were higher in the chemorefractory group than in the chemoresponsive group. CONCLUSION: Jagged-1-activated signaling by APEX1 plays a role in advanced gastric cancer.


Assuntos
DNA Liase (Sítios Apurínicos ou Apirimidínicos)/genética , Resistencia a Medicamentos Antineoplásicos/genética , Proteína Jagged-1/genética , Neoplasias Gástricas/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cisplatino/farmacologia , Fluoruracila/farmacologia , Humanos , Camundongos , Estadiamento de Neoplasias , Estômago/efeitos dos fármacos , Estômago/patologia , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
5.
Anticancer Res ; 39(11): 6097-6105, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31704837

RESUMO

BACKGROUND/AIM: Colorectal cancer (CRC) is one of the most common in the world and its prevalence is rapidly increasing. Jagged-1-activated Notch signaling by apurinic/apyrimidinic endodeoxyribonuclease 1 (APEX1) promotes CRC, and high expression of Jagged-1 is associated with poor prognosis. However, its clinical implication is unknown. The aim of this study was to investigate the clinical role of Jagged-1-activated Notch signaling by APEX1. MATERIALS AND METHODS: The 5-dimethylthiazol-2-yl) 2, 5-diphenyltetrazolium bromide (MTT) assay was used to evaluate the anti-cancer efficacy of 5-fluorouracil (5-FU), oxaliplatin, and irinotecan. Tissue from CRC patients was analyzed to assess the clinical specificity of Jagged-1 activated by APEX1. RESULTS: The half-maximal inhibitory concentration (IC50) in cells co-expressing APEX1 and Jagged-1 cells was higher than that in cells expressing only APEX1. These results indicated that the simultaneous expression of APEX1 and Jagged-1 might be associated with chemoresistance toward 5-FU, oxaliplatin, and irinotecan. Analysis of tissue from CRC patients revealed that high expression of Jagged-1 was associated with a statistically significantly low response to chemotherapy. CONCLUSION: Overexpression of Jagged-1 by APEX1 might serve as a predictor of response to chemotherapy and of poor prognosis, and moreover may be a therapeutic target for chemotherapy of advanced CRC.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias Colorretais/patologia , DNA Liase (Sítios Apurínicos ou Apirimidínicos)/metabolismo , Regulação Neoplásica da Expressão Gênica , Proteína Jagged-1/metabolismo , Receptor Notch1/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Apoptose , Biomarcadores Tumorais/genética , Proliferação de Células , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/metabolismo , DNA Liase (Sítios Apurínicos ou Apirimidínicos)/genética , Feminino , Fluoruracila/administração & dosagem , Seguimentos , Humanos , Irinotecano/administração & dosagem , Proteína Jagged-1/genética , Masculino , Pessoa de Meia-Idade , Oxaliplatina/administração & dosagem , Prognóstico , Receptor Notch1/genética , Estudos Retrospectivos , Taxa de Sobrevida , Células Tumorais Cultivadas
6.
World J Clin Cases ; 7(19): 3039-3046, 2019 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-31624752

RESUMO

BACKGROUND: Bronchobiliary fistula (BBF) is a rare disease characterized by an abnormal connection between the biliary system and bronchi. Traditional causes of BBF include trauma and infections, and more recent causes include malignancies and certain cancer treatments. Ramucirumab is an antivascular endothelial growth factor receptor 2 monoclonal antibody, currently used as a second-line treatment for gastric cancer. CASE SUMMARY: A 43-year-old man visited our hospital with the complaint of jaundice. He was diagnosed with inoperable advanced gastric cancer owing to invasion of the hepatic hilum by the tumor. After percutaneous transhepatic biliary drainage (PTBD) and stent placement, capecitabine and oxaliplatin were administered as first-line palliative chemotherapy. The tumor progressed, and paclitaxel and ramucirumab were administered as second-line chemotherapy. However, on the first day of the second cycle, the patient suddenly developed dyspnea and pneumonia. BBF was diagnosed on the basis of the presence of bilious sputum and the results of computed tomography, and PTBD was repeated. CONCLUSION: This is the first report of BBF after administration of the new antiangiogenic agent ramucirumab.

7.
World J Clin Cases ; 7(24): 4299-4306, 2019 Dec 26.
Artigo em Inglês | MEDLINE | ID: mdl-31911911

RESUMO

BACKGROUND: Post-transplant lymphoproliferative disorder (PTLD) is a fatal complication of solid organ transplantation or allogenic hematopoietic stem cell transplantation that is associated with immunosuppressive therapy. Potential manifestations are diverse, ranging from reactive lymphoid hyperplasia to high-grade lymphoma. PTLD is usually of B-cell origin and associated with Epstein-Barr virus (EBV) infection. Herein, we describe a case of PTLD involving the peritoneal omentum. There has been only case of PTLD as a diffuse large B-cell lymphoma (DLBCL) in the peritoneum. CASE SUMMARY: The patient was a 62-year-old man who had been receiving immunosuppressive therapy with tacrolimus since undergoing a liver transplant 15 years prior. He reported that he had experienced abdominal discomfort and anorexia 1 month prior to the current admission. Abdominal pelvic computed tomography (CT) revealed peritoneal and omental mass-like lesions without bowel obstruction. Ultrasonography-guided biopsy was performed, and he was histologically diagnosed with EBV-negative DLBCL. Positron emission tomography (PET)-CT depicted peritoneum and omentum involvement only, without any lymphadenopathy or organ masses, including in the gastrointestinal tract. Six cycles of chemotherapy with a "R-CHOP" regimen (rituximab-cyclophosphamide, doxorubicin, vincristine, prednisolone) were administered, and PET-CT performed thereafter indicated complete remission. CONCLUSION: This is the first report of isolated peritoneal lymphomatosis defined as PTLD in a liver transplant recipient.

8.
World J Gastroenterol ; 23(33): 6187-6193, 2017 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-28970735

RESUMO

Arterioportal shunt (APS) is an organic communication between the hepatic arterial system and the portal venous system. The APS is one of the major causes of transient hepatic attenuation differences on dynamic computed tomography (CT) or magnetic resonance imaging (MRI). This condition is usually associated with trauma, liver cirrhosis, and malignancies of the liver. However, there has been no report about oxaliplatin-induced APS. A 41-year-old male was diagnosed with Stage IIIB gastric cancer. The patient initially underwent neoadjuvant chemotherapy with capecitabine and oxaliplatin After 3 cycles of therapy, the mass had markedly decreased, and a total gastrectomy with splenectomy was performed. Since the malignancy was locally invasive, the patient was continued on the same regimen of the adjuvant chemotherapy. After 3 more cycles, a computed tomography revealed a 1 cm sized arterial-enhancing nodule in the right lobe of the liver. An MRI revealed an arterial enhancing lesion, and a positron emission tomography CT scan showed a hypermetabolic lesion in the same portion of the liver. We tried to perform a liver biopsy; however, an ultrasonography could not detect any mass. A presumptive diagnosis of an APS due to a recurred cancer was made. We found a similar but slightly different case report of an oxaliplatin-induced liver injury, mimicking a metastatic tumor on an MRI. Based on a prior report, the patient was continued on treatment with adjuvant chemotherapy following discontinuation of oxaliplatin. After 2 cycles, the arterial enhancing liver mass resolved, supporting the final diagnosis of an APS, related to oxaliplatin-induced sinusoidal injury. The patient has not experienced any a relapse after two years of additional follow up recurrent gastric cancer upon interpretation of multiple imaging modalities.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Fístula Arteriovenosa/etiologia , Artéria Hepática/anormalidades , Neoplasias Hepáticas/diagnóstico por imagem , Fígado/irrigação sanguínea , Compostos Organoplatínicos/efeitos adversos , Sistema Porta/anormalidades , Neoplasias Gástricas/terapia , Adulto , Fístula Arteriovenosa/diagnóstico por imagem , Biópsia , Capecitabina/efeitos adversos , Quimioterapia Adjuvante/efeitos adversos , Quimioterapia Adjuvante/métodos , Diagnóstico Diferencial , Fluoruracila , Gastrectomia/métodos , Humanos , Fígado/diagnóstico por imagem , Imageamento por Ressonância Magnética , Masculino , Terapia Neoadjuvante/efeitos adversos , Terapia Neoadjuvante/métodos , Recidiva Local de Neoplasia/diagnóstico por imagem , Oxaliplatina , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Esplenectomia/métodos , Neoplasias Gástricas/diagnóstico por imagem , Neoplasias Gástricas/patologia , Ultrassonografia , Suspensão de Tratamento
9.
Korean J Physiol Pharmacol ; 21(2): 267-273, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28280421

RESUMO

The p53-inducible gene 3 (PIG3), initially identified as a gene downstream of p53, plays an important role in the apoptotic process triggered by p53-mediated reactive oxygen species (ROS) production. Recently, several studies have suggested that PIG3 may play a role in various types of cancer. However, the functional significance of PIG3 in cancer remains unclear. Here, we found that PIG3 was highly expressed in human colon cancer cell lines compared to normal colonderived fibroblasts. Therefore, we attempted to elucidate the functional role of PIG3 in colon cancer. PIG3 overexpression increases the colony formation, migration and invasion ability of HCT116 colon cancer cells. Conversely, these tumorigenic abilities were significantly decreased in in vitro studies with PIG3 knockdown HCT116 cells. PIG3 knockdown also attenuated the growth of mouse xenograft tumors. These results demonstrate that PIG3 is associated with the tumorigenic potential of cancer cells, both in vitro and in vivo, and could play a key oncogenic role in colon cancer.

10.
Sci Rep ; 7: 45290, 2017 03 27.
Artigo em Inglês | MEDLINE | ID: mdl-28345606

RESUMO

Autophagy, the primary recycling pathway within cells, plays a critical role in mitochondrial quality control under normal growth conditions and in the cellular response to stress. Here we provide evidence that 53BP1, a DNA damage response protein, is involved in regulating mitochondrial clearance from the cell via a type of autophagy termed mitophagy. We found that when either human or mouse cells were 53BP1-deficient, there was an increase in mitochondrial abnormalities, as observed through staining intensity, aggregation, and increased mass. Moreover, a 53BP1-depleted cell population included an increased number of cells with a high mitochondrial membrane potential (ΔΨm) relative to controls, suggesting that the loss of 53BP1 prevents initiation of mitophagy thereby leading to the accumulation of damaged mitochondria. Indeed, both 53BP1 and the mitophagy-associated protein LC3 translocated to mitochondria in response to damage induced by the mitochondrial uncoupler carbonyl cyanide m-chlorophenylhydrazone (CCCP). The recruitment of parkin, an E3-ubiquitin ligase, to mitochondria in response to CCCP treatment was significantly decreased in 53BP1-deficient cells. And lastly, using p53-deficient H1299 cells, we confirmed that the role of 53BP1 in mitophagy is independent of p53. These data support a model in which 53BP1 plays an important role in modulating mitochondrial homeostasis and in the clearance of damaged mitochondria.


Assuntos
Autofagia/fisiologia , Mitocôndrias/metabolismo , Proteína 1 de Ligação à Proteína Supressora de Tumor p53/metabolismo , Animais , Linhagem Celular Tumoral , Células HeLa , Humanos , Potencial da Membrana Mitocondrial/fisiologia , Camundongos , Camundongos Knockout , Proteínas Associadas aos Microtúbulos/metabolismo , Proteínas Mitocondriais/metabolismo , Mitofagia/fisiologia , Ubiquitina-Proteína Ligases/metabolismo
11.
Korean J Intern Med ; 32(3): 523-529, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28352060

RESUMO

BACKGROUND/AIMS: Eosinophilia has numerous diverse causes, and in many patients, it is not possible to establish the cause of eosinophilia. Recently, toxocariasis was introduced as one cause of eosinophilia. The aims of this study were to evaluate the prevalence of toxocariasis and the clinical impact of albendazole treatment for toxocariasis in patients suspected of eosinophilia of unknown origin. METHODS: We performed a retrospective chart review. After evaluation of cause of eosinophilia, the patients suspected of eosinophilia of unknown origin performed immunoglobulin G antibody specific assay for the Toxocara canis larval antigen by enzyme-linked immunosorbent assay. RESULTS: This study evaluated 113 patients, 69 patients (61%) were suspected of eosinophilia of unknown origin. Among these 69 patients, the frequency of T. canis infection was very high (45 patients, 65.2%), and albendazole treatment for 45 eosinophilia with toxocariasis was highly effective for a cure of eosinophilia than no albendazole group regardless of steroid (82.3%, p = 0.007). Furthermore, among the nonsteroid treated small group (19 patients), albendazole treatment for eosinophilia were more effective than no albendazole group, too (83.3% vs. 28.6 %, p = 0.045). CONCLUSIONS: The prevalence of toxocariasis was high among patients suspected of eosinophilia of unknown origin; therefore, evaluation for T. canis infection is recommended for patients with eosinophilia of unknown origin. Furthermore, for patients suspected of eosinophilia of unknown origin who have positive results for T. canis, albendazole treatment may be considered a valuable treatment option.


Assuntos
Albendazol/uso terapêutico , Anti-Helmínticos/uso terapêutico , Eosinofilia/parasitologia , Toxocara canis/isolamento & purificação , Toxocaríase/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Eosinofilia/epidemiologia , Feminino , Humanos , Síndrome Hipereosinofílica/parasitologia , Masculino , Pessoa de Meia-Idade , Prevalência , República da Coreia/epidemiologia , Toxocaríase/complicações , Toxocaríase/tratamento farmacológico , Toxocaríase/epidemiologia , Adulto Jovem
12.
Ann Surg Treat Res ; 92(1): 15-22, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28090501

RESUMO

PURPOSE: Biliary cancer is a highly malignant neoplasm with poor prognosis and most patients need to undergo palliative chemotherapy, however major clinical problem associated with the use of chemotherapy is chemoresistance. So far, we aimed at investigating clinical implications of apurinic/apyrimidinic endodeoxyribonuclease 1 (APEX1) and Jagged1 as chemoresistance factors in biliary tract cancer. METHODS: We used 5 human biliary tract cancer cell lines (SNU-245, SNU-308, SNU-478, SNU-1079, and SNU-1196), and investigated the chemosensitivity of APEX1 and Jagged1 through 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay and Western blot. Alternately, the 10 patients of advanced biliary cancer consist of 2 group according to the chemotherapy response examined by immunohistochemistry using APEX1 and Jagged1 antibody, and protein expression level was scored for staining intensity and percent positive cell. RESULTS: The result of MTT assay after APEX1 knockdown showed that strong coexpression of APEX1 and Jagged1 cell line (SNU-245, SNU-1079, and SNU-1196) showed a greater decrease in IC50 of chemotherapeutic agent (5-fluorouracil, gemcitabine and cisplatin). The Western blot analysis of APEX1 and Jagged1 expression in biliary cancer cell lines after APEX1 knockdown definitively demonstrated decreased Jagged1 expression. The APEX1 and Jagged1expression level of immunohistochemistry represented that chemorefractory patients had higher than chemoresponsive patients. CONCLUSION: These results demonstrate that simultaneous high expression of APEX1 and Jagged1 is associated with chemoresistance in biliary cancer and suggest that is a potential therapeutic target for chemoresistance in advanced biliary cancer.

13.
Biochem Biophys Res Commun ; 482(4): 706-712, 2017 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-27866984

RESUMO

Ribonucleotide reductase small subunit p53R2 is a member of the ribonucleotide reductase family that supplies dNTPs for nuclear and mitochondrial DNA replication and repair. Here, we have identified a mitochondrial thioredoxin reductase 2 (TrxR2) as a novel p53R2-binding protein. We demonstrated a direct interaction between the two, and observed that p53R2 stimulated the enzymatic activity of TrxR in vitro. Moreover, TrxR2 activity was significantly lower in p53R2 knockdown cells, and increased when p53R2 was overexpressed, effects that were independent of p53. Furthermore, p53R2 knockdown suppressed UV-induced TrxR activity. These findings suggest that p53R2 acts as a positive regulator of TrxR2 activity in mitochondria both under normal physiological conditions and during the cellular response to DNA damage.


Assuntos
Proteínas de Ciclo Celular/metabolismo , Regulação Enzimológica da Expressão Gênica , Ribonucleotídeo Redutases/metabolismo , Tiorredoxina Redutase 2/metabolismo , Linhagem Celular Tumoral , Dano ao DNA , Reparo do DNA , DNA Mitocondrial/metabolismo , Vetores Genéticos , Humanos , Mitocôndrias/metabolismo , Plasmídeos/metabolismo , Ligação Proteica , RNA Interferente Pequeno/metabolismo , Proteínas Recombinantes/metabolismo , Raios Ultravioleta , Regulação para Cima
14.
J Clin Invest ; 2013 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-23863623

RESUMO

Aberrant expression of apurinic-apyrimidinic endonuclease-1 (APEX1) has been reported in numerous human solid tumors and is positively correlated with cancer progression; however, the role of APEX1 in tumor progression is poorly defined. Here, we show that APEX1 contributes to aggressive colon cancer behavior and functions as an upstream activator in the Jagged1/Notch signaling pathway. APEX1 overexpression or knockdown in human colon cancer cell lines induced profound changes in malignant properties such as cell proliferation, anchorage-independent growth, migration, invasion, and angiogenesis in vitro and in tumor formation and metastasis in mouse xenograft models. These oncogenic effects of APEX1 were mediated by the upregulation of Jagged1, a major Notch ligand. Furthermore, APEX1 expression was associated with Jagged1 in various colon cancer cell lines and in tissues from colon cancer patients. This finding identifies APEX1 as a positive regulator of Jagged1/Notch activity and suggests that it is a potential therapeutic target in colon cancers that exhibit high levels of Jagged1/Notch signaling.

15.
Biochim Biophys Acta ; 1823(12): 2099-108, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22982065

RESUMO

The catalytic subunit of DNA-dependent protein kinase (DNA-PKcs) plays an essential role in double-strand break repair by initially recognizing and binding to DNA breaks. Here, we show that DNA-PKcs interacts with the regulatory γ1 subunit of AMP-activated protein kinase (AMPK), a heterotrimeric enzyme that has been proposed to function as a "fuel gauge" to monitor changes in the energy status of cells and is controlled by the upstream kinases LKB1 and Ca²âº/calmodulin-dependent kinase kinase (CaMKK). In co-immunoprecipitation analyses, DNA-PKcs and AMPKγ1 interacted physically in DNA-PKcs-proficient M059K cells but not in DNA-PKcs-deficient M059J cells. Glucose deprivation-stimulated phosphorylation of AMPKα on Thr172 and of acetyl-CoA carboxylase (ACC), a downstream target of AMPK, is substantially reduced in M059J cells compared with M059K cells. The inhibition or down-regulation of DNA-PKcs by the DNA-PKcs inhibitors, wortmannin and Nu7441, or by DNA-PKcs siRNA caused a marked reduction in AMPK phosphorylation, AMPK activity, and ACC phosphorylation in response to glucose depletion in M059K, WI38, and IMR90 cells. In addition, DNA-DNA-PKcs(-/-) mouse embryonic fibroblasts (MEFs) exhibited decreased AMPK activation in response to glucose-free conditions. Furthermore, the knockdown of DNA-PKcs led to the suppression of AMPK (Thr172) phosphorylation in LKB1-deficient HeLa cells under glucose deprivation. Taken together, these findings support the positive regulation of AMPK activation by DNA-PKcs under glucose-deprived conditions in mammalian cells.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Proteína Quinase Ativada por DNA/metabolismo , Glioma/metabolismo , Glucose/deficiência , Animais , Western Blotting , Células Cultivadas , Reparo do DNA/genética , Proteína Quinase Ativada por DNA/antagonistas & inibidores , Proteína Quinase Ativada por DNA/genética , Embrião de Mamíferos/citologia , Embrião de Mamíferos/efeitos dos fármacos , Embrião de Mamíferos/metabolismo , Inibidores Enzimáticos/farmacologia , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Glioma/genética , Glioma/patologia , Células HeLa , Humanos , Imunoprecipitação , Camundongos , Camundongos Knockout , Fosforilação , Proteínas Serina-Treonina Quinases/deficiência , RNA Interferente Pequeno/genética , Técnicas do Sistema de Duplo-Híbrido
16.
Cancer Sci ; 101(9): 1990-6, 2010 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-20550525

RESUMO

Oncogenic Ras proteins transform cells by way of multiple downstream signaling pathways that promote the genesis of human cancers. However, the exact cellular mechanisms by which downstream targets are regulated are not fully understood. Here, we show that oncogenic Ras reduced Clast1/LR8 transcript levels in mouse NIH3T3 fibroblasts and human WI38 fibroblasts. Clast1/LR8 transcript was undetectable in H460, A549, and H1299 cells showing high Ras activity, but was relatively abundant in DMS53 cells displaying low Ras activity. We also showed that K-Ras siRNA restored Clast1/LR8 expression in H460 and A549 cells, and that inhibitors of DNA methylation and histone deacetylation reversed oncogenic H-Ras-mediated suppression of Clast1/LR8 transcription. Additionally, ectopic expression of Clast1/LR8 inhibited serum-stimulated phosphorylation of ERK1/2 and Akt in H-RasV12-transformed NIH3T3 cells. We further showed that the expression of Clast1/LR8 interfered with oncogenic Ras-induced NIH3T3 cell transformation and invasion. Finally, our results showed that Clast1/LR8 inhibited Ras-induced proliferation of, and tumor formation by, oncogenic H-RasV12-transformed NIH3T3 cells in vivo. This study identifies the downregulation of Clast1/LR8 as a potentially important mechanism by which oncogenic Ras-mediated neoplastic transformation occurs.


Assuntos
Transformação Celular Neoplásica/genética , Regulação para Baixo , Neoplasias Experimentais/genética , Proteínas ras/genética , Acetilação , Animais , Sequência de Bases , Western Blotting , Linhagem Celular , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Metilação de DNA , Feminino , Histonas/metabolismo , Humanos , Camundongos , Camundongos Nus , Dados de Sequência Molecular , Células NIH 3T3 , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Interferência de RNA , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transfecção , Proteínas ras/metabolismo
17.
Korean J Physiol Pharmacol ; 13(5): 349-56, 2009 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-19915696

RESUMO

We previously reported that glial cell line-derived neurotropic factor (GDNF) receptor alpha1 (GFRalpha1) is a direct target of apurinic/apyrimidinic endonuclease 1 (Ape1/Ref-1). In the present study, we further analyzed the physiological roles of Ape1/Ref-1-induced GFRalpha1 expression in Neuro2a mouse neuroblastoma cells. Ape1/Ref-1 expression caused the clustering of GFRalpha1 immunoreactivity in lipid rafts in response to GDNF. We also found that Ret, a downstream target of GFRalpha1, was functionally activated by GDNF in Ape1/Ref-1-expressing cells. Moreover, GDNF promoted the proliferation of Ape1/Ref-1-expressing Neuro2a cells. Furthermore, GFRalpha1-specific RNA experiments demonstrated that the downregulation of GFRalpha1 by siRNA in Ape1/Ref-1-expressing cells impaired the ability of GDNF to phosphorylate Akt and PLCgamma-1 and to stimulate cellular proliferation. These results show an association between Ape1/Ref-1 and GDNF/GFRalpha signaling, and suggest a potential molecular mechanism for the involvement of Ape1/Ref-1 in neuronal proliferation.

18.
Mol Cell Biol ; 29(8): 2264-77, 2009 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-19188437

RESUMO

Apurinic/apyrimidinic endonuclease 1 (Ape1/Ref-1) dysregulation has been identified in several human tumors and in patients with a variety of neurodegenerative diseases. However, the function of Ape1/Ref-1 is unclear. We show here that Ape1/Ref-1 increases the expression of glial cell-derived neurotropic factor (GDNF) receptor alpha1 (GFRalpha1), a key receptor for GDNF. Expression of Ape1/Ref-1 led to an increase in the GDNF responsiveness in human fibroblast. Ape1/Ref-1 induced GFRalpha1 transcription through enhanced binding of NF-kappaB complexes to the GFRalpha1 promoter. GFRalpha1 levels correlate proportionally with Ape1/Ref-1 in cancer cells. The knockdown of endogenous Ape1/Ref-1 in pancreatic cancer cells markedly suppressed GFRalpha1 expression and invasion in response to GNDF, while overexpression of GFRalpha1 restored invasion. In neuronal cells, the Ape1/Ref-1-mediated increase in GDNF responsiveness not only stimulated neurite outgrowth but also protected the cells from beta-amyloid peptide and oxidative stress. Our results show that Ape1/Ref-1 is a novel physiological regulator of GDNF responsiveness, and they also suggest that Ape1/Ref-1-induced GFRalpha1 expression may play important roles in pancreatic cancer progression and neuronal cell survival.


Assuntos
DNA Liase (Sítios Apurínicos ou Apirimidínicos)/fisiologia , Receptores de Fator Neurotrófico Derivado de Linhagem de Célula Glial/genética , Fator Neurotrófico Derivado de Linhagem de Célula Glial/fisiologia , Regulação para Cima/genética , Animais , Linhagem Celular Tumoral , Humanos , Camundongos , NF-kappa B/metabolismo , Invasividade Neoplásica , Neuritos , Neurônios/citologia , Estresse Oxidativo , Neoplasias Pancreáticas/patologia , Regiões Promotoras Genéticas
19.
Cancer Res ; 65(15): 6811-9, 2005 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-16061663

RESUMO

The Ras activation contributes to radioresistance, but the mechanism is unclear. This article shows that the expression of the dominant-positive H-Ras increased the Ku80 level, which is one of the key enzymes involved in repairing dsDNA breaks (DSB). After exposing the cells to ionizing radiation and analyzing them using an electrophoretic mobility shift assay and pulsed-field gel electrophoresis, it was found that activated H-Ras expression in NIH3T3 cells increases the DNA-binding activity of Ku80 and increases the DSB repair activity. Ku80 small interfering RNA expression was shown to reduce the oncogenic H-Ras-mediated increase in the DSBs and suppress the oncogenic H-Ras-mediated resistance of the cells to gamma-ray irradiation, whereas Ku80 overexpression in the NIH3T3 cells significantly increased the radioresistance. These results suggest that the Ku80 expression induced by oncogenic H-Ras seems to play an important role in protecting cells against gamma-ray irradiation.


Assuntos
Antígenos Nucleares/biossíntese , Proteínas de Ligação a DNA/biossíntese , Genes ras/fisiologia , Tolerância a Radiação/fisiologia , Animais , Antígenos Nucleares/genética , Sobrevivência Celular/fisiologia , Sobrevivência Celular/efeitos da radiação , DNA/metabolismo , DNA/efeitos da radiação , Dano ao DNA , Reparo do DNA/efeitos da radiação , Proteínas de Ligação a DNA/genética , Regulação para Baixo , Ecdisterona/análogos & derivados , Raios gama , Regulação da Expressão Gênica , Autoantígeno Ku , Camundongos , Células NIH 3T3 , Análise de Sequência com Séries de Oligonucleotídeos , Regulação para Cima , Proteínas ras/biossíntese , Proteínas ras/genética
20.
Biochem Biophys Res Commun ; 327(1): 225-33, 2005 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-15629453

RESUMO

The level of excision repair cross-complementing 1 (ERCC1) gene expression, which is important in the repair of the cisplatin-DNA adducts, is reported to be related to the level of cisplatin resistance in tumor cells. Therefore, ERCC1 is an attractive target to confer increased cellular sensitivity to cisplatin-based chemotherapy. We designed, synthesized, and utilized small interfering RNAs (siRNAs) that were selective for ERCC1 and investigated their effectiveness in altering the repair capacity of the cells to cisplatin-DNA damage as well as the resistance of the cells to cisplatin. Twenty-four and 48h after transfecting ERCC1 siRNA1 and siRNA2 targeting the two different regions of the ERCC1 transcript, both the ERCC1 mRNA and protein expression were significantly inhibited, whereas the mock or control siRNA had no effect. The suppression of ERCC1 expression in the HeLa S3 cells led to a decrease in the repair activity of cisplatin-induced DNA damage along with a decrease in the cell viability against platinum-based drugs, such as cisplatin, carboplatin, and oxaliplatin. A similar increased sensitivity to cisplatin and decreased repair activity were also observed for siRNA-mediated ERCC1 silencing in the MCF-7 and HCT116 cells. This study is the first to demonstrate the feasibility of utilizing ERCC1 siRNAs to specifically reduce the ERCC1 expression level in human cancer cells and provides direct evidence for the potential use of ERCC1 siRNA as a chemotherapy-sensitizing agent.


Assuntos
Cisplatino/farmacologia , Proteínas de Ligação a DNA/deficiência , Endonucleases/deficiência , Neoplasias/tratamento farmacológico , Neoplasias/genética , RNA Interferente Pequeno/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cisplatino/uso terapêutico , Reparo do DNA , Proteínas de Ligação a DNA/genética , Regulação para Baixo , Endonucleases/genética , Humanos , Neoplasias/patologia , Platina/farmacologia , Interferência de RNA , RNA Interferente Pequeno/genética
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