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1.
J Med Chem ; 2021 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-34813314

RESUMO

Targeting poly(ADP-ribose) polymerase1/2 (PARP1/2) is a promising strategy for the treatment of pancreatic cancer with breast cancer susceptibility gene (BRCA) mutation. Inducing the deficiency of homologous recombination (HR) repair is an effective way to broaden the indication of PARP1/2 inhibitor for more patients with pancreatic cancer. Bromodomain-containing protein 4 (BRD4) repression has been reported to elevate HR deficiency. Therefore, we designed, synthetized, and optimized a dual PARP/BRD4 inhibitor III-16, with a completely new structure and high selectivity against PARP1/2 and BRD4. III-16 showed favorable synergistic antitumor efficacy in pancreatic cancer cells and xenografts by arresting cell cycle progression, inhibiting DNA damage repair, and promoting autophagy-associated cell death. Moreover, III-16 reversed Olaparib-induced acceleration of cell cycle progression and recovery of DNA repair. The advantages of III-16 over Olaparib suggest that dual PARP/BRD4 inhibitors are novel and promising agents for the treatment of advanced pancreatic cancer.

2.
Inorg Chem ; 60(21): 16194-16203, 2021 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-34637309

RESUMO

The multistep synthesis of original antennas incorporating substituted [2.2]paracyclophane (pCp) moieties in the π-conjugated skeleton is described. These antennas, functionalized with an electron donor alkoxy fragment (A1) or with a fused coumarin derivative (A2), are incorporated in a triazacyclonane macrocyclic ligand L1 or L2, respectively, for the design of Eu(III), Yb(III), and Gd(III) complexes. A combined photophysical/theoretical study reveals that A1 presents a charge transfer character via through-space paracyclophane conjugation, whereas A2 presents only local excited states centered on the coumarin-paracyclophane moiety, strongly favoring triplet state population via intersystem crossing. The resulting complexes EuL1 and YbL2 are fully emissive in red and near-infrared, respectively, whereas the GdL2 complex acts as a photosensitizer for the generation of singlet oxygen.

3.
Sensors (Basel) ; 21(17)2021 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-34502619

RESUMO

Gas explosion has always been an important factor restricting coal mine production safety. The application of machine learning techniques in coal mine gas concentration prediction and early warning can effectively prevent gas explosion accidents. Nearly all traditional prediction models use a regression technique to predict gas concentration. Considering there exist very few instances of high gas concentration, the instance distribution of gas concentration would be extremely imbalanced. Therefore, such regression models generally perform poorly in predicting high gas concentration instances. In this study, we consider early warning of gas concentration as a binary-class problem, and divide gas concentration data into warning class and non-warning class according to the concentration threshold. We proposed the probability density machine (PDM) algorithm with excellent adaptability to imbalanced data distribution. In this study, we use the original gas concentration data collected from several monitoring points in a coal mine in Datong city, Shanxi Province, China, to train the PDM model and to compare the model with several class imbalance learning algorithms. The results show that the PDM algorithm is superior to the traditional and state-of-the-art class imbalance learning algorithms, and can produce more accurate early warning results for gas explosion.


Assuntos
Algoritmos , Aprendizado de Máquina , China , Carvão Mineral , Probabilidade
5.
Chirality ; 33(9): 506-527, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34302702

RESUMO

This short review focuses on enantiopure planar chiral [2.2]paracyclophanes (pCps), a fascinating class of molecules that possess an unusual three-dimensional core and intriguing physicochemical properties. In the first part of the review, different synthetic strategies for preparing optically active pCps are described. Although classical resolution methods based on the synthesis and separation of diastereoisomeric products still dominate the field, recent advances involving the kinetic resolution of racemic compounds and the desymmetrization of meso derivatives open up new possibilities to access enantiopure key intermediates on synthetically useful scales. Due to their advantageous properties including high configurational and chemical stability, [2.2]paracyclophanes are increasingly employed in various research fields, ranging from stereoselective synthesis to material sciences. The applications of [2.2]paracyclophanes in asymmetric organocatalysis are described in the second part of the review. While historically enantiopure pCps have been mainly employed by organic chemists as chiral ligands in transition-metal catalysis, these compounds can also be used as efficient catalysts in metal-free reactions and may inspire the development of new transformations in the near future.

6.
Nature ; 593(7860): 586-590, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33981038

RESUMO

Ferroptosis, a form of regulated cell death that is induced by excessive lipid peroxidation, is a key tumour suppression mechanism1-4. Glutathione peroxidase 4 (GPX4)5,6 and ferroptosis suppressor protein 1 (FSP1)7,8 constitute two major ferroptosis defence systems. Here we show that treatment of cancer cells with GPX4 inhibitors results in acute depletion of N-carbamoyl-L-aspartate, a pyrimidine biosynthesis intermediate, with concomitant accumulation of uridine. Supplementation with dihydroorotate or orotate-the substrate and product of dihydroorotate dehydrogenase (DHODH)-attenuates or potentiates ferroptosis induced by inhibition of GPX4, respectively, and these effects are particularly pronounced in cancer cells with low expression of GPX4 (GPX4low). Inactivation of DHODH induces extensive mitochondrial lipid peroxidation and ferroptosis in GPX4low cancer cells, and synergizes with ferroptosis inducers to induce these effects in GPX4high cancer cells. Mechanistically, DHODH operates in parallel to mitochondrial GPX4 (but independently of cytosolic GPX4 or FSP1) to inhibit ferroptosis in the mitochondrial inner membrane by reducing ubiquinone to ubiquinol (a radical-trapping antioxidant with anti-ferroptosis activity). The DHODH inhibitor brequinar selectively suppresses GPX4low tumour growth by inducing ferroptosis, whereas combined treatment with brequinar and sulfasalazine, an FDA-approved drug with ferroptosis-inducing activity, synergistically induces ferroptosis and suppresses GPX4high tumour growth. Our results identify a DHODH-mediated ferroptosis defence mechanism in mitochondria and suggest a therapeutic strategy of targeting ferroptosis in cancer treatment.

7.
Cell Signal ; 84: 110015, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33894313

RESUMO

Patients with prostate cancer (PCa) have a high incidence of relapse and metastasis. Unfortunately, the molecular mechanisms underlying these processes have not been fully elucidated. In our study, we demonstrate that MUC15, a member of the mucin family, is a novel tumor suppressor in PCa that modulates epithelial-mesenchymal transition (EMT) and cancer stemness, contributing to PCa metastasis. First, MUC15 expression was found to be decreased in PCa tissues compared with para-carcinoma tissues. Moreover, we observed that MUC15 suppressed cell migration and invasion, both in vitro and in vivo, but had no effect on cell proliferation. Mechanistically, knockdown of MUC15 increased GSK3ß phosphorylation and promoted ß-catenin nuclear translocation. Therefore, the ß-catenin-specific inhibitors XAV939 and PRI-724 rescued EMT in MUC15-deficient cell lines. Taken together, these results indicate that MUC15 is downregulated in PCa tissues and serves as a potential target to prevent PCa metastasis, which can inhibit EMT and cancer stemness via the GSK3ß/ß-catenin signaling pathway.

8.
Integr Zool ; 16(1): 97-108, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32329566

RESUMO

Masting is an evolutionary strategy used by plants to promote seed survival and/or seed dispersal under animal predation, but its effects on seedling establishment in field condition are rarely tested by long-term experiments incorporating combined effects of seed and animal abundance. Here, we tracked seed production, rodent-mediated seed dispersal, and seedling establishment in Armeniaca sibirica from 2005 to 2014 in a warm-temperate forest in northern China, and examined the effects of seed abundance and per capita seed availability on seed fate and seedling recruitment rate. Our results showed that seed abundance or per capita seed availability generally benefited the seedling recruitment of A. sibirica through increasing dispersal intensity, supporting predator dispersal hypothesis. However, seedling recruitment showed satiated or even dome-shaped association with per capita seed availability, suggesting the benefit to trees would be decreased when seed abundance were too high as compared to rodent abundance (a satiated effect). Our results suggest that the predator dispersal and satiation effects of masting on seedling recruitment can operate together in one system and conditionally change with seed and animal abundance.


Assuntos
Prunus/fisiologia , Roedores/fisiologia , Dispersão de Sementes , Sementes , Animais , Comportamento Animal , China , Comportamento Alimentar , Prunus/crescimento & desenvolvimento , Plântula/crescimento & desenvolvimento
9.
Molecules ; 25(23)2020 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-33287111

RESUMO

Concomitant inhibition of MAPK and PI3K signaling pathways has been recognized as a promising strategy for cancer therapy, which effectively overcomes the drug resistance of MAPK signaling pathway-related inhibitors. Herein, we report the scaffold-hopping generation of a series of 1H-pyrazolo[3,4-d]pyrimidine dual ERK/PI3K inhibitors. Compound 32d was the most promising candidate, with potent inhibitory activities against both ERK2 and PI3Kα which displays superior anti-proliferative profiles against HCT116 and HEC1B cancer cells. Meanwhile, compound 32d possessed acceptable pharmacokinetic profiles and showed more efficacious anti-tumor activity than GDDC-0980 and the corresponding drug combination (BVD-523 + GDDC-0980) in HCT-116 xenograft model, with a tumor growth inhibitory rate of 51% without causing observable toxic effects. All the results indicated that 32d was a highly effective anticancer compound and provided a promising basis for further optimization towards dual ERK/PI3K inhibitors.


Assuntos
Antineoplásicos/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Células HCT116 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Pirimidinas/farmacologia , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos
10.
J Cell Mol Med ; 24(20): 12032-12043, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32902124

RESUMO

Multiple mechanisms contribute to the survival and growth of metastatic castration-resistant prostate cancer (mCRPC) cells without androgen, including androgen receptor splice variants (AR-V) and de novo intratumoral androgen synthesis. AKR1C3 is a critical androgenic enzyme that plays different roles in mCRPC, such as an EMT driver or AR coactivator. However, the relationship and regulatory mechanisms between AKR1C3 and AR-V remain largely unknown. In this study, we observed a positive correlation between AKR1C3 and AR-V7 staining in tissues from prostate rebiopsy at mCRPC. Mechanistically, AKR1C3 interacts with AR-V7 protein in CRPC cells, which can reciprocally inhibit AR-V7 and AKR1C3 protein degradation. Biologically, this complex is essential for in vitro and in vivo tumour growth of CRPC cells after androgen deprivation as it represses B4GALT1, a unique tumour suppressor gene in PCa. Together, this study reveals AKR1C3/AR-V7 complex as a potential therapeutic target in mCRPC.


Assuntos
Membro C3 da Família 1 de alfa-Ceto Redutase/metabolismo , Galactosiltransferases/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/patologia , Receptores Androgênicos/genética , Idoso , Animais , Linhagem Celular Tumoral , Proliferação de Células , Galactosiltransferases/metabolismo , Células HEK293 , Humanos , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Modelos Biológicos , Ligação Proteica , Estabilidade Proteica , Transcrição Genética , Ubiquitina/metabolismo
11.
Cell Death Dis ; 11(5): 336, 2020 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-32382053

RESUMO

Patients with renal cell carcinoma (RCC) often develop distant metastasis and the specific molecular mechanism remains poorly understood. In our study, we demonstrated that MUC15, a subtype of mucins family, could suppress the progression of RCC by inhibiting PI3K/AKT signaling. Firstly, we observed that MUC15 was notably decreased in RCC compared to normal tissue. Furthermore, we showed that MUC15 could negatively modulate the migration and invasion of RCC in vitro and in vivo. Mechanistically, we found that knocking-down of MUC15 could active the PI3K/AKT signaling by increasing the AKT phosphorylation and subsequently increase the mRNA and protein expression of MMP2 and MMP9. Interruption of the AKT pathway with the specific inhibitor LY294002 could reverse the expression of MMPs. Therefore, our study clarify the novel function of MUC15 in RCC, which may provide a new sight to diagnose and prevent RCC metastasis.


Assuntos
Carcinoma de Células Renais/patologia , Neoplasias Renais/patologia , Mucinas/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Animais , Carcinoma de Células Renais/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Regulação para Baixo/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Renais/genética , Metaloproteinases da Matriz/metabolismo , Camundongos Endogâmicos BALB C , Camundongos Nus , Mucinas/genética , Invasividade Neoplásica , Metástase Neoplásica
12.
Cancer Lett ; 471: 135-146, 2020 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-31811906

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies, and chemotherapy is still an important treatment. It is urgent to develop new medicines because of the limitation and side effects of chemotherapy. 2'-Hydroxyflavanone (2HF) is a citrus-bioflavonoid that is considered to have anti-cancer efficacy. Compared to human pancreatic ductal epithelial cells hTERT-HPNE, more significant growth-inhibitory effects were seen in PDAC cells BxPC-3 and MIA PaCa-2. We showed that apoptosis was induced and that the cell cycle was arrested when cells were treated with 2HF. The expression of the molecular proteins cleaved PARP, cleaved Caspase3, Bax, Bcl-2, CyclinD1, and p27 changed correspondingly. Also, we observed anti-metastatic effects and changes in MMP9, E-cadherin, N-cadherin and Vimentin when cells were treated with a low dose of 2HF. Suppression of STAT3 and EGFR phosphorylation was also identified as a result of treatment with a combination of 2HF and EGFR inhibitors. The in vivo antitumor effects in KPC mice were consistent with those observed in vitro. 2HF has impactful anti-cancer efficacy and sensitizes human pancreatic cancer cells to EGFR inhibitors through the inhibition of STAT3.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Carcinoma Ductal Pancreático/tratamento farmacológico , Receptores ErbB/antagonistas & inibidores , Flavanonas/farmacologia , Neoplasias Pancreáticas/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Fator de Transcrição STAT3/antagonistas & inibidores , Animais , Carcinoma Ductal Pancreático/enzimologia , Carcinoma Ductal Pancreático/patologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sinergismo Farmacológico , Receptores ErbB/metabolismo , Flavanonas/administração & dosagem , Humanos , Camundongos , Neoplasias Pancreáticas/enzimologia , Neoplasias Pancreáticas/patologia , Inibidores de Proteínas Quinases/administração & dosagem , Distribuição Aleatória , Fator de Transcrição STAT3/metabolismo
13.
Cell Death Dis ; 10(6): 437, 2019 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-31164632

RESUMO

The prognosis of bladder cancer (BCa) depends on several key factors including anatomical site, tumor grade, and stage. In general, muscle-invasive bladder cancer (MIBC) is associated with higher incidence of distant metastasis compared with Non-muscle-invasive bladder cancer (NMIBC). Treatment outcome of the patients with metastatic BCa has been very poor with ~15% of overall survival rate. Thus, it is apparently important to understand the underlying biology for metastatic progression of BCa. Although epithelial-mesenchymal transition (EMT) has long been implicated in BCa metastasis and treatment resistance, the underlying mechanism is not fully understood. In this study, we have identified that the expression of interferon induced protein with tetratricopeptide repeats 5 (IFIT5) is positively correlated with pathological characteristics, and predicts a poor prognosis of BCa patients. Since the function of IFIT5 in BCa has not yet been characterized, we demonstrate that IFIT5 can induce EMT, promote cell migration and invasion, and increase the expression of ICAM1 in BCa via down-regulation of mature miR-99a. Moreover, ICAM1 is shown as a direct target of miR-99a. Overall, we conclude that IFIT5 is a new oncogene in BCa.


Assuntos
Proliferação de Células/genética , Transição Epitelial-Mesenquimal/genética , Proteínas de Neoplasias/metabolismo , Neoplasias da Bexiga Urinária/metabolismo , Animais , Linhagem Celular Tumoral , Movimento Celular , Progressão da Doença , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Molécula 1 de Adesão Intercelular/genética , Molécula 1 de Adesão Intercelular/metabolismo , Masculino , Camundongos , Camundongos Nus , MicroRNAs/genética , MicroRNAs/metabolismo , Metástase Neoplásica , Proteínas de Neoplasias/genética , Prognóstico , Transplante Heterólogo , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/patologia
14.
Nanomaterials (Basel) ; 9(3)2019 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-30836644

RESUMO

Catalytic hydrolysis of ammonia borane (AB) has been considered as an effective and safe method to generate hydrogen. Development of highly active and low-cost catalysts is one of the key tasks for this technology. In this work, hexagonal CuCo2O4 nanoplatelets with a thickness of approximately 55 nm were prepared. In AB hydrolysis, those nanoplatelets exhibited ultrahigh catalytic activity with turnover frequency (TOF) of 73.4 molhydrogen min-1 molcat-1. As far as we know, this is one of the highest TOF values ever reported for non-noble metal catalysts. In addition, the effects of viscosity and different alkalis on the hydrolysis were also investigated. It is revealed that high viscosity of the reaction medium will retard the hydrolysis reaction. The presence of NaOH, KOH, and Na2CO3 in the reaction solution is favorable for hydrolytic process. In contrast, NH3·H2O will slow down the hydrolysis rate of ammonia borane. This work can provide some novel insight into the design of catalysts with both high performance and low cost. Besides, some findings in the present study can also offer us some information about how to improve the hydrolysis rates by optimizing the hydrolysis condition.

15.
Oncol Rep ; 40(5): 2836-2843, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30226607

RESUMO

Despite the availability of a number of treatment options, certain cases of primary prostate cancer (PCa) will develop into metastatic PCa, in which epithelial­mesenchymal transition (EMT) serves an important role. Recently, a natural flavonoid known as 2'­hydroxyflavanone (2HF) exerts remarkable anticancer activity on various types of cancer. Our previous study demonstrated that 2HF could promote apoptosis and inhibit the proliferation of PCa cells, but whether 2HF is involved in the regulation of EMT, and cell migration and invasion in metastatic PCa remains unknown. The present study used two different metastatic PCa cell lines (PC­3 and DU145) to investigate the effects of 2HF on EMT, and cell migration and invasion. The results demonstrated that 2HF could inhibit EMT, and cell migration and invasion through the Wnt/ß­catenin signaling pathway by suppressing GSK­3ß phosphorylation, ß­catenin expression and transactivation. In conclusion, the present study revealed a novel function of 2HF, which may be used to prevent or treat PCa metastasis.


Assuntos
Flavanonas/farmacologia , Glicogênio Sintase Quinase 3 beta/genética , Neoplasias da Próstata/tratamento farmacológico , beta Catenina/genética , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Metástase Neoplásica , Fosforilação/efeitos dos fármacos , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Via de Sinalização Wnt/efeitos dos fármacos
16.
Cell Death Dis ; 9(9): 881, 2018 08 29.
Artigo em Inglês | MEDLINE | ID: mdl-30158581

RESUMO

Patients with renal cell carcinoma (RCC) often develop resistance to antivascular drugs and eventually succumb to disease. However, the underlying molecular mechanism remains poorly understood. In this study, we demonstrated that RASAL2, a RAS GTPase-activating protein, played a tumor-suppressive role in RCC by targeting tumor angiogenesis. Firstly, we showed that RASAL2 was frequently epigenetically silenced in RCC, and its loss was negatively correlated with overall survival of RCC patients. Furthermore, we discovered that RASAL2 could inhibit RCC angiogenesis in vitro and in vivo. Mechanistically, we identified that RASAL2 could activate GSK3ß by reducing Ser9 phosphorylation and subsequently decrease the expression of c-FOS and vascular endothelial growth factor A (VEGFA). Interruption of the p-GSK3ß/c-FOS pathway with the specific inhibitor or small interfering RNA could reverse the expression of VEGFA, which may provide a new insight to prevent RCC from resistance to antivascular therapy.


Assuntos
Carcinoma de Células Renais/metabolismo , Proteínas de Transporte/metabolismo , Neoplasias Renais/metabolismo , Neovascularização Patológica/metabolismo , Animais , Carcinoma de Células Renais/patologia , Linhagem Celular , Linhagem Celular Tumoral , Epigênese Genética/fisiologia , Proteínas Ativadoras de GTPase/metabolismo , Regulação Neoplásica da Expressão Gênica/fisiologia , Glicogênio Sintase Quinase 3 beta/metabolismo , Células Endoteliais da Veia Umbilical Humana , Humanos , Neoplasias Renais/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neovascularização Patológica/patologia , Fosforilação/fisiologia , Transdução de Sinais/fisiologia , Fator A de Crescimento do Endotélio Vascular/metabolismo
17.
Urol Oncol ; 36(10): 472.e11-472.e20, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30139661

RESUMO

BACKGROUND: AKR1C3, as a crucial androgenic enzyme, facilitates intratumoral androgen biosynthesis and androgen receptor activation in castration-resistant prostate cancer (PCa). The data has shown that AKR1C3 expression is significantly elevated in clinical metastatic PCa specimens, indicating a potential role of AKR1C3 in PCa metastasis. METHODS: C4-2, 22RV1-T, and PC-3 cells with higher AKR1C3 expression were selected and treated with several specific AKR1C3 shRNAs or small molecule inhibitor, and the cell migration and invasion abilities were detected by wound healing assay and Transwell assay. The expression of several epithelial-mesenchymal transition (EMT) markers (i.e., E-cadherin and vimentin) and the related transcription factors (i.e., ZEB1, TWIST1, and SLUG) was examined by Western blot or quantitative PCR assays, and the phosphorylation of AKT or ERK was detected by Western blot. Also, subcutaneous xenografts with 22RV1-T sublines were used to detect in vivo tumor growth, and the expression of E-cadherin, vimentin, and ZEB1 by immunohistochemical staining. The correlation between AKR1C3 and EMT marker expression in clinical specimens was analyzed. RESULTS: AKR1C3 was overexpressed in more aggressive PCa cell lines regardless of the androgen receptor status. Knockdown of AKR1C3 expression or inhibition of AKR1C3 activity could significantly suppress cell migration and invasion abilities in vitro, and increase E-cadherin expression but decrease vimentin expression, in which the phosphorylation of ERK and the EMT-associated transcription factor expression were specifically down-regulated. Also, knockdown of AKR1C3 could suppress PCa tumorigenesis and reverse EMT in vivo. Moreover, there was a significant correlation between AKR1C3 expression and EMT in human PCa specimens from public tissue microarray. CONCLUSIONS: AKR1C3 is a novel EMT driver in PCa metastasis through activating ERK signaling.


Assuntos
Membro C3 da Família 1 de alfa-Ceto Redutase/metabolismo , Transição Epitelial-Mesenquimal/fisiologia , Sistema de Sinalização das MAP Quinases/fisiologia , Neoplasias da Próstata/patologia , Animais , Biomarcadores Tumorais/análise , Linhagem Celular Tumoral , Xenoenxertos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Invasividade Neoplásica/patologia
18.
Cell Signal ; 48: 38-44, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29702203

RESUMO

Muscle-invasive or metastatic bladder cancer (BCa) is a life-threatening disease for patients, and tumor angiogenesis is believed to play a critical role in the progression of BCa. However, its underlying mechanism of tumor angiogenesis is still poorly understood. In this study, we discovered that RASAL2, a RAS GTPase activating protein, could inhibit BCa angiogenesis based on our shRNA/siRNA knockdown or ectopic cDNA expression experiments. Mechanistically, RASAL2 downregulation could enhance the phosphorylation of AKT and then subsequently upregulate the expression of ETS1 and VEGFA. Furthermore, there was a negative correlation between RASAL2 and VEGFA or CD31 expression in subcutaneous xenograft and human BCa specimens. Taken together, we provide a new insight into the molecular mechanism of BCa progression, in which RASAL2 can be a new therapeutic target.


Assuntos
Proteínas de Transporte/fisiologia , Neovascularização Patológica/fisiopatologia , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Proteína Proto-Oncogênica c-ets-1/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Neoplasias da Bexiga Urinária/irrigação sanguínea , Fator A de Crescimento do Endotélio Vascular/metabolismo , Animais , Proteínas de Transporte/genética , Linhagem Celular Tumoral , Proteínas Ativadoras de GTPase , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Xenoenxertos , Células Endoteliais da Veia Umbilical Humana , Humanos , Camundongos Endogâmicos BALB C , Metástase Neoplásica , Neovascularização Patológica/genética , Transdução de Sinais , Neoplasias da Bexiga Urinária/patologia
19.
Org Biomol Chem ; 16(5): 807-815, 2018 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-29326996

RESUMO

An organocatalytic asymmetric [3 + 2] cycloaddition of oxindole-based azomethine ylides with 3-nitro-2H-chromenes has been developed. This reaction provides a facile approach to densely functionalized polycyclic spirooxindole-chromane adducts featuring four contiguous stereogenic centers, including two tetrasubstituted carbon centers. The products were obtained in high yields with good to excellent stereoselectivities (up to 99% yields, 96% ee and >20 : 1 dr). In addition, the spiro[pyrrolidine-2,3'-oxindole]-chromane adducts could be readily derivatized via simple oxidation and reduction treatment. A dual activation working model to illuminate the stereochemical course of the [3 + 2] cycloaddition event is proposed.

20.
Chem Commun (Camb) ; 53(34): 4714-4717, 2017 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-28401208

RESUMO

An organocatalytic asymmetric [3+2] cycloaddition of 3-amino oxindole-based azomethine ylides and α,ß-ynones has been developed. This reaction afforded spiro[dihydropyrrole-2,3'-oxindole] products in high chemical yields with excellent stereoselectivities (up to 99% yields, >20 : 1 dr and >99% ee). Notably, a series of important spiro[pyrrole-oxindole] derivatives were readily obtained via oxidation of the cycloadducts, thus extending the diversity of the products.

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