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1.
Nat Commun ; 11(1): 4496, 2020 09 08.
Artigo em Inglês | MEDLINE | ID: mdl-32901024

RESUMO

Aging is characterized by the loss of homeostasis and the general decline of physiological functions, accompanied by various degenerative diseases and increased rates of mortality. Aging targeting small molecule screens have been performed many times, however, few have focused on endogenous metabolic intermediates-metabolites. Here, using C. elegans lifespan assays, we conducted a worm metabolite screen and identified an eukaryotes conserved metabolite, myo-inositol (MI), to extend lifespan, increase mobility and reduce fat content. Genetic analysis of enzymes in MI metabolic pathway suggest that MI alleviates aging through its derivative PI(4,5)P2. MI and PI(4,5)P2 are precursors of PI(3,4,5)P3, which is negatively related to longevity. The longevity effect of MI is dependent on the tumor suppressor gene, daf-18 (homologous to mouse Pten), independent of its classical pathway downstream genes, akt or daf-16. Furthermore, we found MI effects on aging and lifespan act through mitophagy regulator PTEN induced kinase-1 (pink-1) and mitophagy. MI's anti-aging effect is also conserved in mouse, indicating a conserved mechanism in mammals.


Assuntos
Envelhecimento/metabolismo , Proteínas de Caenorhabditis elegans/metabolismo , Fatores de Transcrição Forkhead/metabolismo , Inositol/metabolismo , Longevidade/fisiologia , PTEN Fosfo-Hidrolase/metabolismo , Envelhecimento/efeitos dos fármacos , Animais , Animais Geneticamente Modificados , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Linhagem Celular Tumoral , Feminino , Fatores de Transcrição Forkhead/genética , Inositol/administração & dosagem , Locomoção/fisiologia , Longevidade/efeitos dos fármacos , Redes e Vias Metabólicas/genética , Metabolômica , Camundongos , Mitofagia/fisiologia , Modelos Animais , Fosfatos de Fosfatidilinositol/metabolismo , Proteínas Quinases/metabolismo , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Interferência de RNA , RNA-Seq
2.
Int J Nanomedicine ; 15: 5131-5146, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32764941

RESUMO

Background: Gene therapy is considered a novel way to treat osteosarcoma, and microRNAs are potential therapeutic targets for osteosarcoma. miR-214 has been found to promote osteosarcoma aggression and metastasis. Graphene oxide (GO) is widely used for gene delivery for the distinct physiochemical properties and minimal cytotoxicity. Methods: Polyethyleneimine (PEI)-functionalized GO complex was well-prepared and loaded with miR-214 inhibitor at different concentrations. The load efficacy was tested by gel retardation assay and the cy3-labeled fluorescence of cellular uptake. The experiments of wound healing, immunofluorescence staining, Western blot, qRT-PCR and immunohistochemical staining were performed to measure the inhibitory effect of the miR-214 inhibitor systematically released from the complexes against MG63, U2OS cells and xenograft tumors. Results: The systematic mechanistic elucidation of the efficient delivery of the miR-214 inhibitor by GO-PEI indicated that the inhibition of cellular miR-214 caused a decrease in osteosarcoma cell invasion and migration and an increase in apoptosis by targeting phosphatase and tensin homolog (PTEN). The synergistic combination of the GO-PEI-miR-214 inhibitor and CDDP chemotherapy showed significant cell death. In a xenograft mouse model, the GO-PEI-miR-214 inhibitor significantly inhibited tumor volume growth. Conclusion: This study indicates the potential of functionalized GO-PEI as a vehicle for miRNA inhibitor delivery to treat osteosarcoma with low toxicity and miR-214 can be a good target for osteosarcoma therapy.


Assuntos
Grafite/química , MicroRNAs/antagonistas & inibidores , Terapia de Alvo Molecular , Osteossarcoma/tratamento farmacológico , PTEN Fosfo-Hidrolase/metabolismo , Polietilenoimina/química , Polietilenoimina/farmacologia , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Neoplasias Ósseas/patologia , Morte Celular/efeitos dos fármacos , Morte Celular/genética , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Movimento Celular/genética , Proliferação de Células/genética , Terapia Combinada , Humanos , Camundongos , MicroRNAs/genética , Osteossarcoma/genética , Osteossarcoma/metabolismo , Osteossarcoma/patologia
3.
Proc Natl Acad Sci U S A ; 117(34): 20538-20548, 2020 08 25.
Artigo em Inglês | MEDLINE | ID: mdl-32788364

RESUMO

Tumor suppressor PTEN (phosphatase and tensin homologue deleted on chromosome 10) levels are frequently found reduced in human cancers, but how PTEN is down-regulated is not fully understood. In addition, although a compelling connection exists between PRL (phosphatase of regenerating liver) 2 and cancer, how this phosphatase induces oncogenesis has been an enigma. Here, we discovered that PRL2 ablation inhibits PTEN heterozygosity-induced tumorigenesis. PRL2 deficiency elevates PTEN and attenuates AKT signaling, leading to decreased proliferation and increased apoptosis in tumors. We also found that high PRL2 expression is correlated with low PTEN level with reduced overall patient survival. Mechanistically, we identified PTEN as a putative PRL2 substrate and demonstrated that PRL2 down-regulates PTEN by dephosphorylating PTEN at Y336, thereby augmenting NEDD4-mediated PTEN ubiquitination and proteasomal degradation. Given the strong cancer susceptibility to subtle reductions in PTEN, the ability of PRL2 to down-regulate PTEN provides a biochemical basis for its oncogenic propensity. The results also suggest that pharmacological targeting of PRL2 could provide a novel therapeutic strategy to restore PTEN, thereby obliterating PTEN deficiency-induced malignancies.


Assuntos
Carcinogênese , Proteínas Imediatamente Precoces/fisiologia , PTEN Fosfo-Hidrolase/metabolismo , Proteínas Tirosina Fosfatases/metabolismo , Proteínas Tirosina Fosfatases/fisiologia , Animais , Feminino , Células HEK293 , Humanos , Longevidade , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Ubiquitina-Proteína Ligases Nedd4/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ubiquitinação
4.
Prostate ; 80(12): 1012-1023, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32649013

RESUMO

BACKGROUND: Small cell neuroendocrine (NE) carcinomas of the prostate classically lose androgen receptor (AR) expression, may harbor loss of the RB1, TP53, and PTEN tumor suppressor genes, and are associated with a poor prognosis. However usual-type adenocarcinomas may also contain areas of NE differentiation, and in this context the molecular features and biological significance are less certain. METHODS: We examined the molecular phenotype and oncologic outcomes of primary prostate adenocarcinomas with ≥5% NE differentiation (≥5% chromogranin A-positive NE cells in any given tumor spot on tissue microarray) using three independent study sets: a set of tumors with paneth cell-like NE differentiation (n = 26), a retrospective case-cohort of intermediate- and high-risk patients enriched for adverse outcomes (n = 267), and primary tumors from a retrospective series of men with eventual castration-resistant metastatic prostate cancer (CRPC) treated with abiraterone or enzalutamide (n = 55). RESULTS: Benign NE cells expressed significantly lower quantified AR levels compared with paired benign luminal cells (P < .001). Similarly, paneth-like NE carcinoma cells or carcinoma cells expressing chromogranin A expressed significantly lower quantified AR levels than paired non-NE carcinoma cells (P < .001). Quantified ERG protein expression, was also lower in chromogranin A-labeled adenocarcinoma cells compared with unlabeled cells (P < .001) and tumors with NE differentiation showed lower gene expression scores for AR activity compared with those without. Despite evidence of lower AR signaling, adenocarcinomas with NE differentiation did not differ by prevalence of TP53 missense mutations, or PTEN or RB1 loss, compared with those without NE differentiation. Finally, NE differentiation was not associated with time to metastasis in intermediate- and high-risk patients (P = .6 on multivariate analysis), nor with progression-free survival in patients with CRPC treated with abiraterone or enzalutamide (P = .9). CONCLUSION: NE differentiation in usual-type primary prostate adenocarcinoma is a molecularly and clinically distinct form of lineage plasticity from that occurring in small cell NE carcinoma.


Assuntos
Células Neuroendócrinas/patologia , Tumores Neuroendócrinos/patologia , Neoplasias da Próstata/patologia , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Carcinoma de Células Pequenas/genética , Carcinoma de Células Pequenas/metabolismo , Carcinoma de Células Pequenas/patologia , Diferenciação Celular/fisiologia , Estudos de Coortes , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Células Neuroendócrinas/metabolismo , Tumores Neuroendócrinos/genética , Tumores Neuroendócrinos/metabolismo , PTEN Fosfo-Hidrolase/genética , PTEN Fosfo-Hidrolase/metabolismo , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/patologia , Receptores Androgênicos/biossíntese , Receptores Androgênicos/genética , Receptores Androgênicos/metabolismo , Proteínas de Ligação a Retinoblastoma/genética , Proteínas de Ligação a Retinoblastoma/metabolismo , Estudos Retrospectivos , Transdução de Sinais , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo
5.
Life Sci ; 256: 118022, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32610163

RESUMO

AIM: We aim to study the anti-apoptotic effect of microRNA-21-5p (miR-21-5p) in the oxidative stress-induced apoptosis of Schwann cells and the relevant mechanism in this research, laying a foundation for the treatment of peripheral neuropathy (PNP). METHODS AND MATERIALS: The oxidative stress model was established by using hydrogen peroxide (H2O2). ROS level were detected by DCFH-DA (2,7-Dichlorodi-hydrofluorescein diacetate). Western blot and fluorescence staining were used to detect the apoptosis and autophagy level. The miR-21-5p overexpression model was established by transfection of miR-21-5p mimics into RSC96 cells. Five groups of control group, H2O2 group, H2O2 + chloroquine (CQ) group, H2O2 + miR-21-5p mimics group, and H2O2 + miR-21-5p mimics+rapamycin (RAPA) group were included in our experiment. KEY FINDINGS: Compared with control group, miR-21-5p was decreased in H2O2-treated RSC96 cells, while autophagy and apoptosis were both promoted. The result revealed that apoptosis was probably triggered by activation of autophagy in H2O2-treated group. In order to verify the relationship between autophagy and apoptosis more accurately, we used CQ to inhibit autophagy. Compared with H2O2-treated group, autophagy and apoptosis were both weakened in H2O2 + CQ group. Subsequently, we found the antiapoptotic effect of miR-21-5p in this model, overexpression of miR-21-5p prevented cells from being damaged by oxidative stress, it induced the decrease of PTEN and the level of autophagy, leading to decreased level of apoptosis. SIGNIFICANCE: The identified relationship between miR-21-5p, apoptosis, and autophagy promotes us to find a new mechanism to improve the treatment for PNP.


Assuntos
Apoptose/genética , Autofagia/genética , MicroRNAs/genética , Estresse Oxidativo/genética , Animais , Linhagem Celular , Regulação da Expressão Gênica , Peróxido de Hidrogênio , PTEN Fosfo-Hidrolase/metabolismo , Doenças do Sistema Nervoso Periférico/genética , Doenças do Sistema Nervoso Periférico/terapia , Ratos , Espécies Reativas de Oxigênio/metabolismo , Células de Schwann/citologia
6.
Nature ; 583(7817): 620-624, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32669709

RESUMO

Approximately 75% of all breast cancers express the oestrogen and/or progesterone receptors. Endocrine therapy is usually effective in these hormone-receptor-positive tumours, but primary and acquired resistance limits its long-term benefit1,2. Here we show that in mouse models of hormone-receptor-positive breast cancer, periodic fasting or a fasting-mimicking diet3-5 enhances the activity of the endocrine therapeutics tamoxifen and fulvestrant by lowering circulating IGF1, insulin and leptin and by inhibiting AKT-mTOR signalling via upregulation of EGR1 and PTEN. When fulvestrant is combined with palbociclib (a cyclin-dependent kinase 4/6 inhibitor), adding periodic cycles of a fasting-mimicking diet promotes long-lasting tumour regression and reverts acquired resistance to drug treatment. Moreover, both fasting and a fasting-mimicking diet prevent tamoxifen-induced endometrial hyperplasia. In patients with hormone-receptor-positive breast cancer receiving oestrogen therapy, cycles of a fasting-mimicking diet cause metabolic changes analogous to those observed in mice, including reduced levels of insulin, leptin and IGF1, with the last two remaining low for extended periods. In mice, these long-lasting effects are associated with long-term anti-cancer activity. These results support further clinical studies of a fasting-mimicking diet as an adjuvant to oestrogen therapy in hormone-receptor-positive breast cancer.


Assuntos
Neoplasias da Mama/dietoterapia , Neoplasias da Mama/tratamento farmacológico , Dietoterapia/métodos , Jejum/fisiologia , Fulvestranto/uso terapêutico , Animais , Fatores Biológicos/sangue , Neoplasias da Mama/patologia , Dieta Saudável/métodos , Modelos Animais de Doenças , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Proteína 1 de Resposta de Crescimento Precoce/metabolismo , Feminino , Fulvestranto/administração & dosagem , Humanos , Insulina/sangue , Fator de Crescimento Insulin-Like I/metabolismo , Leptina/sangue , Células MCF-7 , Camundongos Endogâmicos NOD , Camundongos SCID , PTEN Fosfo-Hidrolase/metabolismo , Piperazinas/administração & dosagem , Piperazinas/uso terapêutico , Piridinas/administração & dosagem , Piridinas/uso terapêutico , Receptores Estrogênicos , Receptores de Progesterona , Tamoxifeno/efeitos adversos , Tamoxifeno/uso terapêutico , Ensaios Antitumorais Modelo de Xenoenxerto
7.
J Cancer Res Ther ; 16(3): 513-516, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32719259

RESUMO

Background: Altered molecular signaling pathways in ameloblastoma have been identified to play a pivotal role in the mechanism of oncogenesis, differentiation, and tumor progression. Phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin pathway is one of the signaling pathways that are associated with the pathogenesis of ameloblastoma. Phosphatase and tensin homolog (PTEN) controls cell migration and proliferation. It monitors the level of the Akt and maintains cellular integrity. The present study was aimed to study the immunoexpression of PTEN in ameloblastoma to understand its role in the pathogenesis of ameloblastoma. Materials and Methods: Twenty cases of ameloblastoma and ten cases of normal tooth germ were subjected to immunohistochemical staining against PTEN. Results: Strong PTEN immunopositivity was seen in the tooth germs, while weak positivity was seen in the ameloblastoma. The immunoscore for PTEN was calculated by adding the percentage score and the intensity score. Seventeen cases showed the reduced PTEN expression in the epithelial component of ameloblastoma. The unpaired t-test showed a statistically significant difference in the mean PTEN immunoscore in tooth germ and ameloblastoma. Conclusion: The study showed reduced PTEN immunoreactivity, which plays a role in the pathogenesis of ameloblastoma, through Akt pathway.


Assuntos
Ameloblastoma/patologia , Biomarcadores Tumorais/metabolismo , Neoplasias Maxilomandibulares/patologia , PTEN Fosfo-Hidrolase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Adolescente , Adulto , Idoso , Ameloblastoma/metabolismo , Estudos de Casos e Controles , Diferenciação Celular , Feminino , Humanos , Imuno-Histoquímica , Lactente , Neoplasias Maxilomandibulares/metabolismo , Masculino , Pessoa de Meia-Idade , Transdução de Sinais , Adulto Jovem
8.
Gen Physiol Biophys ; 39(3): 259-268, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32525819

RESUMO

Ischemic stroke is one of the most common public health problems worldwide. The aim of the present study was to investigate the role of miR-19a and its possible target genes in SK-N-SH cells subjected to oxygen-glucose deprivation/re-oxygenation (OGD/R) injury. SK-N-SH cells are a suitable model for host transfection. SK-N-SH cells were transfected with miR-19a mimic or inhibitor and PTEN-small interfering (si) RNA in order to alter the expression of miR-19a, PTEN and AKT. The expression changes in acute cerebral ischemic injury (ACII) were verified using RT-qPCR and Western blotting. Expression changes and the association between miR-19a and PTEN following OGD/R were also assessed using a double luciferase analysis. In addition, cell viability and apoptosis were measured using an MTT and flow cytometry. miR-19a was downregulated; however, PTEN was markedly increased following OGD/R injury. miR-19a mimics increased cell viability, decreased cell apoptosis of SK-N-SH cells following OGD/R, which effects was similar to PTEN siRNA; however, miR-19a inhibitor had the opposite roles with miR-19a mimics. The present study provides novel information about the cell apoptosis and invasion mechanisms associated with the miR-19a/PTEN/AKT pathway and may present a potential therapeutic approach for OGD/R injury.


Assuntos
MicroRNAs/genética , Neuroproteção , PTEN Fosfo-Hidrolase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Apoptose , Hipóxia Celular , Linhagem Celular Tumoral , Sobrevivência Celular , Glucose , Humanos , Oxigênio
9.
Prostate ; 80(11): 906-914, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32519789

RESUMO

BACKGROUND: There is convincing evidence that men with advanced prostate cancer experience improved quality of life as a result of exercise therapy, although there is limited preclinical, and no clinical, data to directly support the notion that exercise training improves prostate cancer prognosis or outcome. The aim of this study was to investigate the effect of regular exercise training on the early stages of prostate cancer progression, as well as assessing whether alterations to prostate cancer metabolism are induced by exercise. METHODS: Mice with prostate-specific deletion of Pten (Pten-/- ) remained sedentary or underwent 6 weeks of endurance exercise training or high-intensity exercise training involving treadmill running. At the conclusion of the training period, the prostate lobes were excised. A portion of fresh tissue was used to assess glucose, glutamine, and fatty acid metabolism by radiometric techniques and a second portion was fixed for histopathology. RESULTS: Despite the implementation of an effective exercise regime, as confirmed by improvements in running capacity, neither prostate mass, cell proliferation or the incidence of high-grade prostate intraepithelial hyperplasia or noninvasive carcinoma in situ were significantly different between groups. Similarly, neither glucose uptake, oxidation and de novo lipogenesis, glutamine oxidation, or fatty acid uptake, oxidation and storage into various lipids were significantly different in prostate tissue obtained from untrained and exercise trained mice. CONCLUSIONS: These results show that 6 weeks of moderate or high-intensity exercise training does not alter substrate metabolism in the prostate or slow the progression of Pten-null prostate cancer. These results question whether exercise is a useful therapy to prevent or delay prostate cancer progression.


Assuntos
PTEN Fosfo-Hidrolase/deficiência , Condicionamento Físico Animal , Neoplasias da Próstata/terapia , Animais , Progressão da Doença , Masculino , Camundongos , Camundongos Knockout , PTEN Fosfo-Hidrolase/genética , PTEN Fosfo-Hidrolase/metabolismo , Neoplasias da Próstata/enzimologia , Neoplasias da Próstata/patologia
10.
Life Sci ; 256: 117924, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32522568

RESUMO

AIMS: Osteoarthritis (OA) is a common degenerative joint disease characterized by cartilage degeneration and joint inflammation. As its pathogenesis remains unclear, there are no effective treatments established. Circular RNA (circRNA), microRNA (miRNA), and other noncoding RNAs participate in OA development; however, the effects and mechanisms of circRNA and miRNA in OA remain unknown. MAIN METHODS: Cartilage miRNA was examined in patients with and without OA. KEY FINDINGS: CircRNA-9119 and phosphatase and tensin homolog (PTEN) expression decreased in OA-affected cartilage and interleukin (IL)-1ß-induced chondrocytes, and miR-26a expression significantly decreased in normal cells and tissues. CircRNA-9119 overexpression restored chondrocyte growth, whereas IL-1ß treatment impaired chondrocyte growth. Annexin V-FITC & PI flow cytometry and Bcl-2/Bax ratio measurement indicated that the apoptosis of IL-1ß-treated articular chondrocytes was decreased by circRNA-9119 upregulation. Bioinformatic prediction and the dual-luciferase reporter assay indicated that circRNA-9119 served as a miR-26a sponge and that miR-26a targeted the 3'-UTR of PTEN. Transfection of chondrocytes with a circRNA-9119-overexpressing vector revealed downregulation of miR-26a expression. Furthermore, circRNA-9119 overexpression induced PTEN expression. In addition, a miR-26a mimic induced IL-1ß-induced chondrocyte apoptosis, and circRNA-9119 overexpression inhibited IL-1ß-induced chondrocyte apoptosis. SIGNIFICANCE: CircRNA-9119 is an important regulator of IL-1ß-treated chondrocytes through the miR-26a/PTEN axis, possibly contributing to OA development.


Assuntos
Condrócitos/metabolismo , Interleucina-1beta/metabolismo , Osteoartrite/tratamento farmacológico , Substâncias Protetoras/metabolismo , RNA Circular/metabolismo , Regiões 3' não Traduzidas , Apoptose/efeitos dos fármacos , Cartilagem/metabolismo , Cartilagem Articular/metabolismo , Linhagem Celular , Condrócitos/citologia , Regulação para Baixo , Matriz Extracelular/metabolismo , Humanos , MicroRNAs/genética , PTEN Fosfo-Hidrolase/metabolismo , Monoéster Fosfórico Hidrolases/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Regulação para Cima , Proteína X Associada a bcl-2/metabolismo
11.
PLoS One ; 15(5): e0233163, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32413098

RESUMO

Inositol polyphosphate-4-phosphatase type II (INPP4B) is a dual-specificity phosphatase that acts as a tumor suppressor in multiple cancers. INPP4B dephosphorylates phospholipids at the 4th position of the inositol ring and inhibits AKT and PKC signaling by hydrolyzing of PI(3,4)P2 and PI(4,5)P2, respectively. INPP4B protein phosphatase targets include phospho-tyrosines on Akt and phospho-serine and phospho-threonine on PTEN. INPP4B is highly expressed in testes, suggesting its role in testes development and physiology. The objective of this study was to determine whether Inpp4b deletion impacts testicular function in mice. In testis, Inpp4b expression was the highest in postmeiotic germ cells in both mice and men. The testes of Inpp4b knockout male mice were significantly smaller compared to the testes of wild-type (WT) males. Inpp4b-/- males produced fewer mature sperm cells compared to WT, and this difference increased with age and high fat diet (HFD). Reduction in early steroidogenic enzymes and luteinizing hormone (LH) receptor gene expression was detected, although androgen receptor (AR) protein level was similar in WT and Inpp4b-/- testes. Germ cell apoptosis was significantly increased in the knockout mice, while expression of meiotic marker γH2A.X was decreased. Our data demonstrate that INPP4B plays a role in maintenance of male germ cell differentiation and protects testis functions against deleterious effects of aging and high fat diet.


Assuntos
Monoéster Fosfórico Hidrolases/metabolismo , Espermatogênese/genética , Espermatozoides/metabolismo , Testículo/metabolismo , Animais , Apoptose/genética , Citocinas/metabolismo , Dieta Hiperlipídica/efeitos adversos , Regulação da Expressão Gênica no Desenvolvimento/genética , Histonas/metabolismo , Humanos , Masculino , Meiose/genética , Camundongos , Camundongos Knockout , PTEN Fosfo-Hidrolase/genética , PTEN Fosfo-Hidrolase/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Monoéster Fosfórico Hidrolases/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA-Seq , Receptores Androgênicos/metabolismo , Receptores do LH/genética , Receptores do LH/metabolismo , Análise de Célula Única , Contagem de Espermatozoides , Testículo/crescimento & desenvolvimento
12.
Arch Biochem Biophys ; 689: 108412, 2020 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-32445778

RESUMO

BACKGROUND: Glioblastoma (GB) is the most common neoplasm in the brain. Curcumin, as a known polyphenolic compound extracted from turmeric, is a chemotherapy used in some cancer treatments in China. However, the effect of curcumin on the survivability of GB cells remains to be elucidated. METHODS: We performed a CCK8 assay to detect the viability of GB cells following treatments with curcumin and examined the migration and invasion the ability of these cells using the wound-healing and transwell invasion assays. The cell proliferation and apoptotic proteins were detected by Western blot analyses. We utilized a glioblastoma-xenograft mouse model to assess cell proliferation following curcumin treatment. RESULTS: We found that curcumin inhibited the proliferation, migration, and invasion of U251 and U87 GB cells. We detected that curcumin decreased p-AKT and p-mTOR protein expression, and promoted the apoptosis of U251 and U87 GB cells. Further, we found that curcumin promoted the PTEN and p53 expression, as the tumor suppressor genes. In addition, we administered curcumin to nude mice and found that curcumin decreased the tumor volume, caused necrosis of tumor tissue, and significantly enhanced the PTEN and p53 expression in vivo. CONCLUSIONS: These results indicated that curcumin inhibited proliferation by decreasing the p-AKT/p-mTOR pathway and promoted apoptosis by increasing the PTEN and p53 expression. Our study provided the molecular mechanisms by which curcumin inhibited glioblastoma and its targeted interventions.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Proliferação de Células/efeitos dos fármacos , Curcumina/uso terapêutico , Glioblastoma/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Animais , Antineoplásicos/farmacologia , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Curcumina/farmacologia , Feminino , Glioblastoma/metabolismo , Glioblastoma/patologia , Humanos , Camundongos , Camundongos Nus , PTEN Fosfo-Hidrolase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Serina-Treonina Quinases TOR/metabolismo
13.
Nat Commun ; 11(1): 1720, 2020 04 06.
Artigo em Inglês | MEDLINE | ID: mdl-32249768

RESUMO

Nuclear localization of PTEN is essential for its tumor suppressive role, and loss of nuclear PTEN is more prominent than cytoplasmic PTEN in many kinds of cancers. However, nuclear PTEN-specific regulatory mechanisms were rarely reported. Based on the finding that nuclear PTEN is more unstable than cytoplasmic PTEN, here we identify that F-box only protein 22 (FBXO22) induces ubiquitylation of nuclear but not cytoplasmic PTEN at lysine 221, which is responsible for the degradation of nuclear PTEN. FBXO22 plays a tumor-promoting role by ubiquitylating and degrading nuclear PTEN. In accordance, FBXO22 is overexpressed in various cancer types, and contributes to nuclear PTEN downregulation in colorectal cancer tissues. Cumulatively, our study reports the mechanism to specifically regulate the stability of nuclear PTEN, which would provide the opportunity for developing therapeutic strategies aiming to achieve complete reactivation of PTEN as a tumor suppressor.


Assuntos
Carcinogênese/genética , Núcleo Celular/metabolismo , Transformação Celular Neoplásica/genética , Neoplasias Colorretais/metabolismo , Proteínas F-Box/metabolismo , PTEN Fosfo-Hidrolase/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Animais , Linhagem Celular Tumoral , Cromatografia Líquida , Neoplasias Colorretais/genética , Citoplasma/metabolismo , Proteínas F-Box/genética , Feminino , Humanos , Camundongos , Camundongos Endogâmicos NOD , Camundongos Nus , Camundongos SCID , PTEN Fosfo-Hidrolase/química , PTEN Fosfo-Hidrolase/genética , RNA Interferente Pequeno , Receptores Citoplasmáticos e Nucleares/genética , Transdução de Sinais/genética , Espectrometria de Massas em Tandem , Análise Serial de Tecidos , Transplante Heterólogo , Ubiquitinação
14.
Hum Cell ; 33(3): 569-581, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32253621

RESUMO

Osteoporosis (OP) is a systemic bone metabolic disorder, which negatively affects the quality of life in the elders and postmenopausal females. Healthy volunteers and postmenopausal females with OP were enrolled in the present study. Bone densitometry (BMD) was detected by dual-energy X-ray absorptiometry (DXA). CD14+PBMCs and C2C12 cells were cultured to induce osteoclast differentiation and osteoblast differentiation, respectively. The interaction between miR­140-3p and PTEN was predicted and verified by TargetScan 7.2 and dual luciferase reporter assay, respectively. miRNA/RNA level and protein level were detected by quantitative real-time polymerase chain reaction (qRT-PCR) and western blot, respectively. Cell proliferation and apoptosis were detected by 5-ethynyl-2'-deoxyuridine (EdU) staining and flow cytometry, respectively. Cell differentiation of CD14+PBMCs and C2C12 cells were detected by tartrate-resistant acid phosphatase (TRAP) staining and alizarin red staining, respectively. The activity of alkaline phosphatase (ALP) was detected by ALP assay. Differences were observed in age, body mass index (BMI), and BMD between the OP group and the control group. Higher miR­140-3p level and lower PTEN level were found in PBMCs of OP group compared to control group; there was a negative correlation between them in the serum of OP group. miR-140-3p targeted and downregulated the expression of PTEN. miR-140-3p inhibitor inhibited cell proliferation, differentiation, and promoted cell apoptosis of CD14+PBMCs; while promoted cell proliferation, differentiation and inhibited cell apoptosis of C2C12 cells, by targeting PTEN and inactivating PTEN/PI3K/AKT signaling pathway. These findings suggested a potential therapeutic role of miR-140-3p in the treatment of patients with OP.


Assuntos
Osteoporose/genética , Osteoporose/patologia , PTEN Fosfo-Hidrolase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/genética , Apoptose , Diferenciação Celular , Proliferação de Células , Células Cultivadas , Células HEK293 , Humanos , Terapia de Alvo Molecular , Osteoblastos , Osteoclastos , Osteoporose/tratamento farmacológico , Fosfatidilinositol 3-Quinases/metabolismo
15.
Nat Commun ; 11(1): 1797, 2020 04 14.
Artigo em Inglês | MEDLINE | ID: mdl-32286273

RESUMO

Mutations that inactivate negative translation regulators cause autism spectrum disorders (ASD), which predominantly affect males and exhibit social interaction and communication deficits and repetitive behaviors. However, the cells that cause ASD through elevated protein synthesis resulting from these mutations remain unknown. Here we employ conditional overexpression of translation initiation factor eIF4E to increase protein synthesis in specific brain cells. We show that exaggerated translation in microglia, but not neurons or astrocytes, leads to autism-like behaviors in male mice. Although microglial eIF4E overexpression elevates translation in both sexes, it only increases microglial density and size in males, accompanied by microglial shift from homeostatic to a functional state with enhanced phagocytic capacity but reduced motility and synapse engulfment. Consequently, cortical neurons in the mice have higher synapse density, neuroligins, and excitation-to-inhibition ratio compared to control mice. We propose that functional perturbation of male microglia is an important cause for sex-biased ASD.


Assuntos
Transtorno Autístico/metabolismo , Comportamento Animal , Microglia/metabolismo , Biossíntese de Proteínas , Animais , Proteínas de Ligação ao Cálcio/metabolismo , Movimento Celular , Feminino , Perfilação da Expressão Gênica , Genótipo , Homeostase , Masculino , Camundongos Knockout , Proteínas dos Microfilamentos/metabolismo , Neurônios/metabolismo , PTEN Fosfo-Hidrolase/metabolismo , Fagocitose , Córtex Pré-Frontal/metabolismo , Córtex Pré-Frontal/ultraestrutura , Comportamento Social , Sinapses/metabolismo
16.
Life Sci ; 253: 117718, 2020 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-32343998

RESUMO

AIMS: This study aimed to explore the functions of miR-455-3p, PTEN, and PI3K/AKT pathway in osteoarthritis. MATERIALS AND METHODS: We used the human bone marrow stem cell (BMSC), healthy chondrocytes, osteoarthritis chondrocytes (OA), and the IL-1ß/TNF-α-treated chondrocyte model to explore the relationship between miR-455-3p and PTEN. Mimic or inhibitor was used to transfect chondrocytes to determine whether miR-455-3p can regulate PTEN and influence COL2A1 and MMP13. Apoptosis was detected by flow cytometry. A luciferase report was applied to verify the targeted binding. KO mice were applied to investigate PTEN and pAKT expression and the effect on chondrocytes in vivo. KEY FINDINGS: MiR-455-3p and PTEN were reverse in chondrogenesis and healthy cartilage versus OA cartilage. Similar trends were noted in IL-1ß model. PTEN and MMP13 decreased and COL2A1 increased after overexpressing miR-455-3p, whereas the inhibition showed opposite results. Flow cytometry showed that miR-455-3p could reduce the apoptosis of chondrocytes. The results of luciferase revealed that miR-455-3p could affect fluorescence activity of PTEN by targeting its 3'-UTR. Finally, we found a marked increased in the expression of PTEN in KO mice relative to WT mice, while pAKT levels decreased. SIGNIFICANCE: It can be supported that miR-455-3p can reduce the apoptosis of chondrocytes and alleviate OA through regulating PI3K/AKT pathway, which may be expected to be a target for the treatment of osteoarthritis.


Assuntos
Apoptose/genética , Condrócitos/patologia , MicroRNAs/genética , Osteoartrite/patologia , Regiões 3' não Traduzidas/genética , Adolescente , Adulto , Animais , Feminino , Humanos , Masculino , Camundongos , Camundongos Knockout , Osteoartrite/genética , PTEN Fosfo-Hidrolase/metabolismo , Fosfatidilinositol 3-Quinase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Adulto Jovem
17.
Nat Commun ; 11(1): 1880, 2020 04 20.
Artigo em Inglês | MEDLINE | ID: mdl-32312982

RESUMO

PI3K/AKT signaling is known to regulate cancer metabolism, but whether metabolic feedback regulates the PI3K/AKT pathway is unclear. Here, we demonstrate the important reciprocal crosstalk between the PI3K/AKT signal and pentose phosphate pathway (PPP) branching metabolic pathways. PI3K/AKT activation stabilizes G6PD, the rate-limiting enzyme of the PPP, by inhibiting the newly identified E3 ligase TIRM21 and promotes the PPP. PPP metabolites, in turn, reinforce AKT activation and further promote cancer metabolic reprogramming by blocking the expression of the AKT inhibitor PHLDA3. Knockout of TRIM21 or PHLDA3 promotes crosstalk and cell proliferation. Importantly, PTEN null human cancer cells and in vivo murine models are sensitive to anti-PPP treatments, suggesting the importance of the PPP in maintaining AKT activation even in the presence of a constitutively activated PI3K pathway. Our study suggests that blockade of this reciprocal crosstalk mechanism may have a therapeutic benefit for cancers with PTEN loss or PI3K/AKT activation.


Assuntos
Proteínas Nucleares/metabolismo , Via de Pentose Fosfato/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ribonucleoproteínas/metabolismo , Células A549 , Animais , Apoptose , Linhagem Celular Tumoral , Proliferação de Células , Sobrevivência Celular , Modelos Animais de Doenças , Técnicas de Inativação de Genes , Glucosefosfato Desidrogenase , Humanos , Masculino , Camundongos , Transplante de Neoplasias , Neoplasias/metabolismo , Proteínas Nucleares/farmacologia , PTEN Fosfo-Hidrolase/metabolismo , Via de Pentose Fosfato/fisiologia , Ribonucleoproteínas/farmacologia , Transdução de Sinais
18.
Oncol Rep ; 43(6): 1885-1896, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32236585

RESUMO

Epigallocatechin­3­gallate (EGCG), a polyphenol present in green tea, exhibits anticancer effects in various types of cancer. A number of studies have focused on the effects of EGCG on lung cancer, but not ovarian cancer. Previous reports have implicated that EGCG suppressed ovarian cancer cell proliferation and induced apoptosis, but its potential anticancer mechanisms and signaling pathways remain unclear. Thus, it is necessary to determine the anti­ovarian cancer effects of EGCG and explore the underlying mechanisms. In the present study, EGCG exerted stronger proliferation inhibition on SKOV3 cells compared with A549 cells and induced apoptosis in SKOV3 cells, as well as upregulated PTEN expression and downregulated the expression of phosphoinositide­dependent kinase­1 (PDK1), phosphor (p)­AKT and p­mTOR. These effects were reversed by the PTEN inhibitor VO­Ohpic trihydrate. The results of the mouse xenograft experiment demonstrated that 50 mg/kg EGCG exhibited increased tumor growth inhibition compared with 5 mg/kg paclitaxel. In addition, PTEN expression was upregulated, whereas the expression levels of PDK1, p­AKT and p­mTOR were downregulated in the EGCG treatment group compared with those in untreated mice in vivo. In conclusion, the results of the present study provided a new underlying mechanism of the effect of EGCG on ovarian cancer and may lead to the development of EGCG as a candidate drug for ovarian cancer therapy.


Assuntos
Antineoplásicos Fitogênicos/administração & dosagem , Catequina/análogos & derivados , Neoplasias Ovarianas/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Células A549 , Animais , Antineoplásicos Fitogênicos/farmacologia , Catequina/administração & dosagem , Catequina/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Camundongos , Neoplasias Ovarianas/metabolismo , PTEN Fosfo-Hidrolase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
19.
Gene ; 747: 144553, 2020 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-32165307

RESUMO

Cisplatin is commonly used for lung cancer treatment. However, acquire resistance to cisplatin results in reduced therapy efficacy. Tripartite motif-containing 59 (TRIM59), acting as an oncogene in non-small cell lung cancer (NSCLC), induces chemoresistance in breast cancer cells. Here, the mechanism by which TRIM59 mediates cisplatin resistance was determined. We demonstrated that cisplatin-resistant NSCLC cell line (A549/DDP) had higher expression of TRIM59 than its parental cell line (A549). As indicated by cell apoptosis assay, TRIM59 overexpression in A549 cells resulted in an increased cisplatin resistance, while TRIM59 downregulation in A549/DDP cells led to an decreased cisplatin resistence. A549/DDP cells with TIMR59 knockdown was more sensitive to cisplatin treatment in a xenograft model. Moreover, A549/DDP cells exhibited increased glucose uptake, lactate production, and hexokinase 2 (HK2, an important glycolytic pathway enzyme) expression than A549 cells. The glycolysis was increased by TRIM59 overexpression in A549 cell, and decreased by TRIM59 knockdown in A549/DDP cells. 3-Bromopyruvate Acid (3-BrPA), an inhibitor of HK2, significantly enhanced cisplatin-sensitivity in A549 cells overexpressing TRIM59. Furthermore, both TRIM59 and HK2 expression was higher in cisplatin-resistant NSCLC tissues than in non-resistant ones, and mRNA expression of these two molecules was positively correlated in NSCLC tissues. The changes of PTEN and phosphorylation of AKT (p-AKT), a critical upstream regulator of HK2, were also consistent with HK2 expression. Immunoprecipiation experiments showed the interaction between TRIM59 and PTEN in A549/DDP cells, and that TRIM59 knockdown suppressed the ubiquitination of PTEN. Collectively, the present study indicates that TRIM59 knockdown reverses high glycolysis rate and cisplatin resistance in A549/DDP cells through the regulation of PTEN/AKT/HK2 and may provide insights into overcoming cancer resistance to cisplatin treatment.


Assuntos
Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos , Técnicas de Silenciamento de Genes , Hexoquinase/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , PTEN Fosfo-Hidrolase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas com Motivo Tripartido/metabolismo , Células A549 , Animais , Apoptose/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/genética , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glicólise/efeitos dos fármacos , Glicólise/genética , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Camundongos Endogâmicos BALB C , Camundongos Nus , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ubiquitinação
20.
J Cancer Res Clin Oncol ; 146(4): 809-820, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32146564

RESUMO

PURPOSE: MicroRNAs (miRNAs) participate in a variety of biological processes, including tumorigenesis, progression, invasion, and drug resistance to multiple cancers. Phosphatase and tensin homolog (PTEN) is a cancer suppressor gene that has been certified to be regulated by miRNAs in various tumors, including colorectal cancer (CRC). In this review, we screened articles focusing on low PTEN expression in CRC, observed the expression of related miRNAs, analyzed their correlation and relationship with clinicopathological features, and discussed the possibility of these miRNAs as prognostic molecules. METHODS: We conducted a systematic search for articles published in the Web of Science, PubMed and EBSCO databases between January 1, 2002, and July 18, 2019. We identified these studies by using combinations of the following index entries and key words: 'colorectal tumor OR colorectal neoplasm OR colorectal carcinoma OR colorectal cancer OR CRC', 'protein tyrosine phosphatase OR PTEN', and 'microRNA OR MiRNA OR miRNA OR MicroRNA'. Moreover, we evaluated the underlying association between alterations in PTEN and CRC prognosis. RESULTS: PTEN expression was obviously lower in CRC tissues than in normal mucosa. However, PTEN expression did not differ significantly between adenoma and normal tissues. PTEN tends to be negatively associated with tumor size and metastasis. MiR-21, miR-200a, miR-543, miR-32, miR-92a, miR-26a, miR-106a and miR-181a were correlated with the downregulation of PTEN. MiR-26a, miR-106a and miR-181a were obviously higher in CRC tissues than in normal tissues, while PTEN was downregulated in CRC tissues. Additionally, miRNAs were mainly positively correlated with distant metastasis, followed by TNM stage. The relationship between miRNAs and tumor differentiation is controversial. However, there were no significant differences between miRNAs and either sex or age. CONCLUSIONS: The loss of PTEN may be a diagnostic factor for CRC patients. The above-mentioned miRNAs may function as oncogenes in CRC and represent potential targets for CRC therapy. However, further prospective clinical studies are necessary.


Assuntos
Neoplasias Colorretais/genética , MicroRNAs/genética , PTEN Fosfo-Hidrolase/genética , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Neoplasias Colorretais/enzimologia , Humanos , MicroRNAs/metabolismo , PTEN Fosfo-Hidrolase/metabolismo
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