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Osteosarcoma (OS) is a highly aggressive malignant bone tumor that mainly occurs in adolescents. At present, chemotherapy is the most commonly used method in clinical practice to treat OS. However, due to drug resistance, toxicity and long-term side effects, chemotherapy can't always provide sufficient benefits for OS patients, especially those with metastasis and recurrence. Natural products have long been an excellent source of anti-tumor drug development. In the current study, we evaluated the anti-OS activity of Echinatin (Ecn), a natural active component from the roots and rhizomes of licorice, and explored the possible mechanism. We found that Ecn inhibited the proliferation of human OS cells and blocked cell cycle at S phase. In addition, Ecn suppressed the migration and invasion, while induced the apoptosis of human OS cells. However, Ecn had less cytotoxicity against normal cells. Moreover, Ecn inhibited the xenograft tumor growth of OS cells in vivo. Mechanistically, Ecn inactivated Wnt/ß-catenin signaling pathway while activated p38 signaling pathway. ß-catenin over-expression and the p38 inhibitor SB203580 both attenuated the inhibitory effect of Ecn on OS cells. Notably, we demonstrated that Ecn exhibited synergistic inhibitory effect with cisplatin (DDP) on OS cells in vitro and in vivo. Therefore, our results suggest that Ecn may exert anti-OS effects at least partly through regulating Wnt/ß-catenin and p38 signaling pathways. Most meaningfully, the results obtained suggest a potential strategy to improve the DDP-induced tumor-killing effect on OS cells by combining with Ecn.
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Neoplasias Ósseas , Osteossarcoma , Adolescente , Humanos , beta Catenina/metabolismo , Proliferação de Células , Osteossarcoma/metabolismo , Via de Sinalização Wnt , Apoptose , Neoplasias Ósseas/metabolismo , Linhagem Celular Tumoral , Movimento CelularRESUMO
Osteosarcoma (OS) is the most prevalent malignant bone tumor with poor prognosis. Developing new drugs for the chemotherapy of OS has been a focal point and a major obstacle of OS treatment. Nitazoxanide (NTZ), a conventional anti-parasitic agent, has got increasingly noticed because of its favorable antitumor potential. Herein, we investigated the effect of NTZ on human OS cells in vitro and in vivo. The results obtained in vitro showed that NTZ inhibited the proliferation, migration and invasion, arrested cell cycle at G1 phase, while induced apoptosis of OS cells. Mechanistically, NTZ suppressed the activity of AKT/mTOR and Wnt/ß-catenin signaling pathways of OS cells. Consistent with the results in vitro, orthotopic implantation model of 143B OS cells further confirmed that NTZ inhibited OS cells growth and lung metastasis in vivo. Notably, NTZ caused no apparent damage to normal cells/tissues. In conclusion, NTZ may inhibit tumor growth and metastasis of human OS cells through suppressing AKT/mTOR and Wnt/ß-catenin signaling pathways.
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Neoplasias Ósseas , Osteossarcoma , Apoptose , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/patologia , Ciclo Celular , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Humanos , Nitrocompostos , Osteossarcoma/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Serina-Treonina Quinases TOR/farmacologia , Serina-Treonina Quinases TOR/uso terapêutico , Tiazóis , Via de Sinalização Wnt , beta Catenina/metabolismoRESUMO
BACKGROUND: Circular RNAs (circRNAs) dysregulation has been revealed to function in the pathological processes of cancers. Herein, the role and mechanisms of hsa_circ_0002082 in breast cancer (BC) progression were elucidated. METHODS: In vivo and in vitro functional experiments were conducted, and the interaction between miR-508-3p and hsa_circ_0002082 or Centromere Protein F (CENPF) was elucidated. RESULTS: Hsa_circ_0002082 expression was higher in BC tissues and cell lines. Functionally, knockdown of hsa_circ_0002082 induced apoptosis and suppressed proliferation and metastasis in BC cells in vitro. Mechanistically, hsa_circ_0002082 targeted miR-508-3p, which was confirmed to be decreased in BC. MiR-508-3p overexpression suppressed BC cell malignant phenotypes, moreover, inhibition of miR-508-3p attenuated the anticancer action of hsa_circ_0002082 silencing on BC cells. Besides that, miR-508-3p targeted CENPF, CENPF was highly expressed in BC, CENPF up-regulation reversed the suppressive impacts of miR-508-3p on BC cell growth and metastasis. Besides, hsa_circ_0002082 silencing impeded BC growth in nude mice. CONCLUSION: Knockdown of hsa_circ_0002082 suppresses breast cancer growth and metastasis by miR-508-3p/CENPF axis, suggesting that hsa_circ_0002082 may be a promising target for breast cancer treatment.
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MicroRNAs , Neoplasias , Animais , Camundongos , Linhagem Celular Tumoral , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica , Camundongos Nus , MicroRNAs/genética , MicroRNAs/metabolismo , Neoplasias/genética , Humanos , RNA Circular/genéticaRESUMO
Liver plays an essential role in regulating lipid metabolism, and chronically disturbed hepatic metabolism may cause obesity and metabolic syndrome, which may lead to non-alcoholic fatty liver disease (NAFLD). Increasing evidence indicates long non-coding RNAs (lncRNAs) play an important role in energy metabolism. Here, we investigated the role of lncRNA H19 in hepatic lipid metabolism and its potential association with NAFLD. We found that H19 was up-regulated in oleic acid-induced steatosis and during the development of high-fat diet (HFD)-induced NAFLD. Exogenous overexpression of H19 in hepatocytes induced lipid accumulation and up-regulated the expression of numerous genes involved in lipid synthesis, storage and breakdown, while silencing endogenous H19 led to a decreased lipid accumulation in hepatocytes. Mechanistically, H19 was shown to promote hepatic steatosis by up-regulating lipogenic transcription factor MLXIPL. Silencing Mlxipl diminished H19-induced lipid accumulation in hepatocytes. Furthermore, H19-induced lipid accumulation was effectively inhibited by PI3K/mTOR inhibitor PF-04691502. Accordingly, H19 overexpression in hepatocytes up-regulated most components of the mTORC1 signalling axis, which were inhibited by silencing endogenous H19. In vivo hepatocyte implantation studies further confirm that H19 promoted hepatic steatosis by up-regulating both mTORC1 signalling axis and MLXIPL transcriptional network. Collectively, these findings strongly suggest that H19 may play an important role in regulating hepatic lipid metabolism and may serve as a potential therapeutic target for NAFLD.
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Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/metabolismo , Hepatócitos/metabolismo , Hepatócitos/patologia , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Hepatopatia Gordurosa não Alcoólica/genética , RNA Longo não Codificante/metabolismo , Transdução de Sinais , Animais , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genética , Modelos Animais de Doenças , Inativação Gênica , Células HEK293 , Humanos , Metabolismo dos Lipídeos/genética , Masculino , Camundongos Endogâmicos C57BL , Ácido Oleico , RNA Longo não Codificante/genética , Triglicerídeos/metabolismo , Regulação para Cima/genéticaRESUMO
Mesenchymal stem cells (MSCs) are multipotent progenitors that can differentiate into a variety of cell types under proper stimuli. Bone morphogenetic protein 9 (BMP9) is able to simultaneously induce both adipogenic and osteogenic differentiation of MSCs although the regulatory molecules involved remain to be fully identified and characterized. Heme oxygenase 1 (Hmox1) plays an essential role not only in fat metabolism, but also in bone development. In the present study, we investigated the functional role of Hmox1 in BMP9-induced osteogenic/adipogenic differentiation in MSCs line C3H10T1/2 and probed the possible mechanism involved. We found that BMP9 promoted the endogenous expression of Hmox1 in C3H10T1/2 cells. Overexpression of Hmox1 or cobalt protoporphyrin (CoPP), an inducer of Hmox1, increased BMP9-induced osteogenic differentiation in vitro. Subcutaneous stem cell implantation in nude mice further confirmed that Hmox1 potentiated BMP9-induced ectopic bone formation in vivo. In contrast, Hmox1 reduced BMP9-induced adipogenic differentiation in C3H10T1/2 cells. Although had no obvious effect on BMP9-induced Smad1/5/8 phosphorylation, Hmox1 enhanced phosphorylation of p38, and AKT, while decreased phosphorylation of ERK1/2. Furthermore, Hmox1 increased total ß-catenin protein level, and promoted the nuclear translocation of ß-catenin in C3H10T1/2 cells. Taken together, our study strongly suggests that Hmox1 is likely to potentiate osteogenic differentiation and yet decrease adipogenic differentiation induced by BMP9 possibly through regulation of multiple signaling pathways.
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Adipogenia , Diferenciação Celular , Fator 2 de Diferenciação de Crescimento/metabolismo , Heme Oxigenase-1/metabolismo , Proteínas de Membrana/metabolismo , Células-Tronco Mesenquimais/citologia , Osteogênese , Animais , Células Cultivadas , Feminino , Fator 2 de Diferenciação de Crescimento/genética , Heme Oxigenase-1/genética , Proteínas de Membrana/genética , Células-Tronco Mesenquimais/metabolismo , Camundongos , Camundongos Endogâmicos C3H , Camundongos Nus , Fosforilação , Transdução de SinaisRESUMO
As one of the least studied bone morphogenetic proteins (BMPs), BMP9 is highly capable of promoting osteogenic differentiation. However, the underlying mechanism involved remains largely unknown. Recent studies have demonstrated that RUNX1 (runt-related transcription factor 1) is essential in osteoblast/chondrocyte maturation. In this study, we investigated the function of RUNX1 in BMP9-induced osteogenic of murine mesenchymal stem cell line (C3H10T1/2) and murine multi-lineage cell lines (C2C12 and MEFs). Our data showed that BMP9 promoted the endogenous expression of RUNX1 in C3H10T1/2, C2C12 and MEFs. Moreover, RUNX1 was probably a direct target of BMP9/Smad signaling. BMP9-induced osteogenic differentiation was enhanced by overexpression of RUNX1, whereas inhibited by knockdown RUNX1 in C3H10T1/2, C2C12 and MEFs. Further mechanism studies demonstrated that RUNX1 might affect BMP9-induced phosphorylation of Smad1/5/8, but not the phosphorylation of p38 and ERK1/2.Our results suggest that RUNX1 may be an essential modulator in BMP9- induced osteogenic differentiation of MSCs (Mesenchymal stem cells).
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Diferenciação Celular , Subunidade alfa 2 de Fator de Ligação ao Core/metabolismo , Fibroblastos/citologia , Fator 2 de Diferenciação de Crescimento/metabolismo , Células-Tronco Mesenquimais/citologia , Mioblastos/citologia , Osteogênese , Animais , Linhagem Celular , Fibroblastos/metabolismo , Células HCT116 , Humanos , Sistema de Sinalização das MAP Quinases , Células-Tronco Mesenquimais/metabolismo , Camundongos , Mioblastos/metabolismo , Transdução de Sinais , Proteínas Smad/metabolismoRESUMO
BACKGROUND/AIMS: BMP9 is highly capable of promoting osteogenic differentiation of mesenchymal stem cells (MSCs) although the molecular mechanism involved is largely unknown. Here, we explored the detail role of PKA/CREB signaling in BMP9-induced osteogenic differentiation. METHODS: Activation status of PKA/CREB signaling is assessed by nonradioactive assay and Western blot. Using PKA inhibitors and a dominant negative protein of CREB (A-CREB), we investigated the effect of PKA/CREB signaling on BMP9-induced osteogenic differentiation. RESULTS: We found that BMP9 promotes PKA activity and enhances CREB phosphorylation in MSCs. BMP9 is shown to down-regulate protein kinase A inhibitor γ (PKIγ) expression. We demonstrated that PKA inhibitors suppress BMP9-induced early osteogenic marker alkaline phosphatase (ALP) activity in MSCs as well as late osteogenic markers osteopontin (OPN), osteocalcin (OCN) and matrix mineralization. We found that PKA inhibitor reduces BMP9-induced Runx2 activation and p38 phosphorylation in MSCs. Lastly, interference of CREB function by A-CREB decreased BMP9-induced osteogenic differentiation as well. CONCLUSION: Our results revealed that BMP9 may activate PKA/CREB signaling in MSCs through suppression of PKIγ expression. It is noteworthy that inhibition of PKA/CREB signaling may impair BMP9-induced osteogenic differentiation of MSCs, implying that activation of PKA/CREB signaling is required for BMP9 osteoinductive activity.
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Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Fator 2 de Diferenciação de Crescimento/farmacologia , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Células-Tronco Mesenquimais/efeitos dos fármacos , Osteogênese/efeitos dos fármacos , Animais , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Células-Tronco Mesenquimais/citologia , Camundongos , Fosforilação/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacosRESUMO
Bone and soft tissue sarcomas are a group of histologically heterogeneous and relatively uncommon tumors. To explore their genetic origins, we sequenced the exomes of 13 osteosarcomas, eight myxoid liposarcomas (MLPS), and seven synovial sarcomas (SYN). These tumors had few genetic alterations (median of 10.8). Nevertheless, clear examples of driver gene mutations were observed, including canonical mutations in TP53, PIK3CA, SETD2, AKT1, and subclonal mutation in FBXW7. Of particular interest were mutations in H3F3A, encoding the variant histone H3.3. Mutations in this gene have only been previously observed in gliomas. Loss of heterozygosity of exomic regions was extensive in osteosarcomas but rare in SYN and MLPS. These results provide intriguing nucleotide-level information on these relatively uncommon neoplasms and highlight pathways that help explain their pathogenesis.
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Neoplasias Ósseas/genética , Lipossarcoma Mixoide/genética , Osteossarcoma/genética , Sarcoma Sinovial/genética , Sarcoma/genética , Adolescente , Adulto , Idoso , Criança , Exoma , Humanos , Perda de Heterozigosidade , Pessoa de Meia-Idade , MutaçãoRESUMO
Bone morphogenetic proteins (BMPs), which belong to the transforming growth factor-ß superfamily, regulate a wide range of cellular responses including cell proliferation, differentiation, adhesion, migration, and apoptosis. BMP9, the latest BMP to be discovered, is reportedly expressed in a variety of human carcinoma cell lines, but the role of BMP9 in breast cancer has not been fully clarified. In a previous study, BMP9 was found to inhibit the growth, migration, and invasiveness of MDA-MB-231 breast cancer cells. In the current study, the effect of BMP9 on the bone metastasis of breast cancer cells was investigated. After absent or low expression of BMP9 was detected in the MDA-MB-231 breast cancer cells and breast non-tumor adjacent tissues using Western blot and immunohistochemistry, In our previous study, BMP9 could inhibit the proliferation and invasiveness of breast cancer cells MDA-MB-231 in vitro and in vivo. This paper shows that BMP9 inhibit the bone metastasis of breast cancer cells by activating the BMP/Smad signaling pathway and downregulating connective tissue growth factor (CTGF); however, when CTGF expression was maintained, the inhibitory effect of BMP9 on the MDA-MB-231 cells was abolished. Together, these observations indicate that BMP9 is an important mediator of breast cancer bone metastasis and a potential therapeutic target for treating this deadly disease.
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Apoptose/genética , Neoplasias da Mama/genética , Fator de Crescimento do Tecido Conjuntivo/biossíntese , Fatores de Diferenciação de Crescimento/metabolismo , Neoplasias Ósseas/secundário , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Proliferação de Células , Fator de Crescimento do Tecido Conjuntivo/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Fator 2 de Diferenciação de Crescimento , Fatores de Diferenciação de Crescimento/genética , HumanosRESUMO
Bladder cancer (BC) is the most common malignant tumor in urinary system. Although chemotherapy is one of the most important adjuvant treatments for BC, drug resistance, non-specific toxicity and severe side effects are the major obstacles to BC chemotherapy. Natural products have always been a leading resource of antitumor drug discovery, with the advantages of excellent effectiveness, low toxicity, multi-targeting potency and easy availability. In this study, we evaluated the potential anti-tumor effect of securinine (SEC), a natural alkaloid from Securinega suffruticosa, on BC cells in vitro and in vivo, and delineated the underlying mechanism. We found that SEC inhibited the proliferation, migration and invasion, induced the apoptosis of BC cells in vitro, and retarded the xenograft tumor growth of BC cell in vivo. Notably, SEC had a promising safety profile because it presented no or low toxicity on normal cells and mice. Mechanistically, SEC inactivated Wnt/ß-catenin signaling pathway while activated p38 and JNK signaling pathway. Moreover, ß-catenin overexpression, the p38 inhibitor SB203580 and the JNK inhibitor SP600125 both mitigated the inhibitory effect of SEC on BC cells. Furthermore, we demonstrated a synergistic inhibitory effect of SEC and gemcitabine (GEM) on BC cells in vitro and in vivo. Taken together, our findings suggest that SEC may exert anti-BC cell effect at least through the activation of p38 and JNK signaling pathways, and the inhibition of Wnt/ß-catenin signaling pathway. More meaningfully, the findings indicate that GEM-induced BC cell killing can be enhanced by combining with SEC.
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Antineoplásicos , Azepinas , Compostos Heterocíclicos de Anel em Ponte , Lactonas , Piperidinas , Neoplasias da Bexiga Urinária , Humanos , Animais , Camundongos , Via de Sinalização Wnt , Sistema de Sinalização das MAP Quinases , Proliferação de Células , Antineoplásicos/farmacologia , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/patologia , Linhagem Celular Tumoral , beta Catenina/metabolismo , Movimento Celular , ApoptoseRESUMO
Exosomal microRNAs (exomiRNAs) have emerged as promising biomarkers for the early clinical diagnosis of osteoporosis. However, their limited abundance and short length in peripheral blood present significant challenges for the accurate detection of exomiRNAs. Herein, we have designed and implemented an efficacious fluorescence-based biosensor for the highly sensitive detection of exomiRNA associated with osteoporosis, leveraging the enhancing 3D DNA walker-induced CRISPR/Cas12a technology. The engineered DNA walker is capable of efficiently transforming target exomiRNA into amplifying DNA strands, thereby enhancing the sensitivity of the developed biosensor. Concurrently, the liberated DNA strands serve as activators to trigger Cas12a trans-cleavage activity, culminating in a significantly amplified fluorescent signal for the highly sensitive detection of exomiRNA-214. Under optimal conditions, the devised technology demonstrated the capacity to detect target exomiRNA-214 at concentrations as low as 20.42 fM, encompassing a wide linear range extending from 50.0 fM to 10.0 nM. Moreover, the fluorescence-based biosensor could accurately differentiate between healthy individuals and osteoporosis patients via the detection of exomiRNA-214, which was in agreement with RT-qPCR results. As such, this biosensing technology offers promise as a valuable tool for the early diagnosis of osteoporosis.
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MicroRNAs , Osteoporose , Humanos , Sistemas CRISPR-Cas/genética , DNA/genética , Osteoporose/diagnóstico , Osteoporose/genética , TecnologiaRESUMO
Osteosarcoma is a primary solid bone malignancy, and surgery + chemotherapy is the most commonly used treatment. However, chemotherapeutic drugs can cause a range of side effects. Casticin, a polymethoxyflavonoid, has anti-tumor therapeutic effects. This study is aim to investigate the anti-osteosarcoma activity of casticin and explore the mechanism. Crystal violet staining, MTT assay, colony formation assay, wound healing assay, transwell assay, hoechst 33,258 staining, and flow cytometry analysis were used to investigate the effects of casticin on proliferation, migration, invasion, and apoptosis of osteosarcoma cells in vitro. The intracellular Fe2+, ROS, MDA, GSH/GSSG content changes were detected using the corresponding assay kits. The mRNA sequencing + bioinformatics analysis and western blot were used to detect the possible mechanism. We found that casticin caused G2/M phase cell cycle arrest in human osteosarcoma cells, inhibited the migration and invasion, and induced cell apoptosis and ferroptosis. Mechanistic studies showed the ferroptosis pathway was enriched stronger than apoptosis. Casticin up-regulated the expression of HMOX1, LC3 and NCOA4, meanwhile it activated MAPK signaling pathways. Animal experiments proved that casticin also inhibited the growth and metastasis of osteosarcoma cell xenograft tumor in vivo. In conclusion, casticin can induce ferroptosis in osteosarcoma cells through Fe2+ overload and ROS production mediated by HMOX1 and LC3-NCOA4. This provides a new strategy for osteosarcoma treatment.
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Ferroptose , Heme Oxigenase-1 , Osteossarcoma , Espécies Reativas de Oxigênio , Animais , Humanos , Masculino , Camundongos , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/patologia , Linhagem Celular Tumoral , Ferroptose/efeitos dos fármacos , Ferroptose/fisiologia , Flavonoides/farmacologia , Heme Oxigenase-1/metabolismo , Heme Oxigenase-1/genética , Ferro/metabolismo , Camundongos Endogâmicos BALB C , Camundongos Nus , Osteossarcoma/tratamento farmacológico , Osteossarcoma/metabolismo , Osteossarcoma/patologia , Espécies Reativas de Oxigênio/metabolismoRESUMO
Diseases, such as bone nonunion with bone defects, osteoporosis, etc, seriously endanger people's quality of life, and bone tissue engineering based on mesenchymal stem cells is an effective method to solve such problems. Several studies have shown that BMP9 can effectively promote osteogenic differentiation of MSCs, but the underlying molecular mechanisms are still unclear. Gli1 and Gli2 were important transcription factors and play an important role in the Hedgehog signaling pathway. In this study, we investigated the role of Gli1 and Gli2 in BMP9-induced osteogenic differentiation of MSCs. We found that inhibition of Gli1 and Gli2 weakened BMP9-induced osteogenic differentiation of MSCs, and early osteogenic markers (alkaline phosphatase, ALP), late osteogenic markers (calcium salt deposition), the expression of pivotal osteogenic markers were attenuated, and inhibition of Gli1 and Gli2 weakened the expression of p-Smad1/5/8 and p-p38 induced by BMP9. In conclusion, our study shows that Gli1 and Gli2 play an important role in BMP9-induced osteogenic differentiation.
Assuntos
Células-Tronco Mesenquimais , Osteogênese , Proteína GLI1 em Dedos de Zinco , Proteína Gli2 com Dedos de Zinco , Animais , Camundongos , Diferenciação Celular , Fator 2 de Diferenciação de Crescimento/metabolismo , Fator 2 de Diferenciação de Crescimento/farmacologia , Proteínas Hedgehog/metabolismo , Proteínas Hedgehog/farmacologia , Qualidade de Vida , Proteína GLI1 em Dedos de Zinco/genética , Proteína GLI1 em Dedos de Zinco/metabolismo , Proteína GLI1 em Dedos de Zinco/farmacologiaRESUMO
Subsequently to the publication of the above paper, a concerned reader drew to the authors' attention that there were a number of overlapping data panels featured in the cellular images shown in Fig. 2C on p. 1644, and Figs. 3D and 4 on p. 1645, such that data that were allegedly obtained under different experimental conditions appeared to have been derived from some of the same original sources. Given the number of errors that had been made during the compilation of the figures in this article, the Editor of International Journal of Molecular Medicine has decided that this article should be retracted from the publication owing to a lack of overall confidence in the presented data. The authors were asked for an explanation to account for these concerns, but the Editorial Office did not receive a reply. The Editor apologizes to the readership for any inconvenience that might result from the retraction of this article. [International Journal of Molecular Medicine 35: 16411650, 2015; DOI: 10.3892/ijmm.2015.2172].
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[This corrects the article DOI: 10.1016/j.gendis.2020.07.014.].
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Osteosarcoma (OS) is a primary malignant tumor of bone. Chemotherapy is one of the crucial approaches to prevent its metastasis and improve prognosis. Despite continuous improvements in the clinical treatment of OS, tumor resistance and metastasis remain dominant clinical challenges. Macropinocytosis, a form of non-selective nutrient endocytosis, has received increasing attention as a novel target for cancer therapy, yet its role in OS cells remains obscure. Benzethonium chloride (BZN) is an FDA-approved antiseptic and bactericide with broad-spectrum anticancer effects. Here, we described that BZN suppressed the proliferation, migration, and invasion of OS cells in vitro and in vivo, but simultaneously promoted the massive accumulation of cytoplasmic vacuoles as well. Mechanistically, BZN repressed the ERK1/2 signaling pathway, and the ERK1/2 activator partially neutralized the inhibitory effect of BZN on OS cells. Subsequently, we demonstrated that vacuoles originated from macropinocytosis and indicated that OS cells might employ macropinocytosis as a compensatory survival mechanism in response to BZN. Remarkably, macropinocytosis inhibitors enhanced the anti-OS effect of BZN in vitro and in vivo. In conclusion, our results suggest that BZN may inhibit OS cells by repressing the ERK1/2 signaling pathway and propose a potential strategy to enhance the BZN-induced inhibitory effect by suppressing macropinocytosis.
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Osteosarcoma (OS) is the most common malignant bone tumor worldwide and is associated with a poor prognosis, often being accompanied by lung metastasis at an early stage. At present, there are several sideeffects associated with the OS clinical treatment of OS, with the treatment effects often being unsatisfactory. Thus, there is an urgent need for the development of safe and effective novel drugs for the treatment of OS. Schisandrin B (Sch B) has been previously demonstrated to exhibit antitumor properties. The present study was focused on the effects of Sch B on OS cells (143B, MG63, Saos2 and U2OS) in vitro and in vivo, and also on its possible antitumor mechanisms. In cell experiments, it was revealed that Sch B inhibited OS cell proliferation, migration and invasion, and increased OS cell apoptosis. As regards its biosafety, no notable effects of Sch B on the vitality of normal cells were observed. Mechanistically, it was demonstrated that Sch B blocked OS cell proliferation in the G1 phase. Subsequently, by using established animal models, it was revealed that Sch B significantly inhibited OS growth and lung metastasis in vivo. In summary, the results of the present study revealed that Sch B inhibited OS cell proliferation, migration and invasion, and promoted apoptosis via the inhibition of the Wnt/ßcatenin and PI3K/Akt signaling pathways, without causing any noticeable toxic effects on healthy cells at the therapeutic concentrations used. These findings suggest that Sch B has potential for use as a novel agent for the clinical treatment of OS.
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Lignanas/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Osteossarcoma/tratamento farmacológico , Fosfatidilinositol 3-Quinases/metabolismo , Compostos Policíclicos/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Via de Sinalização Wnt/efeitos dos fármacos , beta Catenina/metabolismo , Animais , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/patologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Ciclo-Octanos/farmacologia , Modelos Animais de Doenças , Humanos , Neoplasias Pulmonares/secundário , Camundongos , Osteossarcoma/patologiaRESUMO
Although there are many therapeutic strategies such as surgery and chemotherapy, the prognosis of osteosarcoma (OS) is still far from being satisfactory. It is urgent to develop more effective, tolerable and safe drugs for the treatment of OS. In the present study, we investigated the anti-OS activity of Alantolactone (ALT), a natural eucalyptone sesquiterpene lactone mainly exists in Inula helenium, and probed the possible mechanism involved. We demonstrated that ALT significantly inhibited cell proliferation of various human OS cell lines while had relative lower cytotoxicity against normal cells. Then, we validated that ALT reduced migration, decreased invasion possibly through reversing epithelial mesenchymal transition (EMT) process and suppressing Matrix metalloproteinases (MMPs). Moreover, we confirmed that ALT promoted apoptosis and arrested cell cycle at G2/M phase of human OS cells in vitro. In addition, we confirmed that ALT restrained tumor growth and metastasis of OS 143 cells in a xenograft model in vivo. Mechanistically, ALT inhibited the activity of Wnt/ß-catenin and p38, ERK1/2 and JNK Mitogen Activated Protein Kinases (MAPKs) signal pathway. Notably, the combination of ALT and Wnt/ß-catenin inhibitor, as well as the combination of ALT and MAPKs inhibitors resulted in a synergistically effect on inhibiting the proliferation, migration and invasion of OS cells. Collectively, our results validate the ALT may inhibit proliferation, metastasis and promotes apoptosis of human OS cells possibly through suppressing Wnt/ß-Catenin and MAPKs signaling pathways.
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Bone morphogenetic protein 9 (BMP9), also named as growth differentiation factor 2 (GDF-2), is the strongest cytokine that promotes osteogenic differentiation in the BMP family, and has broad clinical application value. Nevertheless, the mechanism of BMP9 promotes osteogenic differentiation remain unclear. TAZ, a transcriptional co-activator, has great effects on cell proliferation, differentiation, and stem cell self-renewal. In this research, we investigated the effects of TAZ in BMP9-induced osteogenic differentiation of mesenchymal stem cell line C3H10T1/2 (MSCs) and murine multi-lineage cell lines C2C12 and MEFs (MMCs) and explored its possible mechanisms. This study has found that BMP9 induces the expression of TAZ and promotes its nuclear translocation. Meanwhile, our study found that Ad-TAZ and TM-25659, a TAZ agonist, can enhance the osteogenic differentiation of MSCs and MMCs induced by BMP9. Conversely, Ad-si-TAZ and verteporfin, an inhibitor of TAZ, have the contradictory effect. Likewise, the promotion of TAZ to the BMP9-induced ectopic bone formation in vivo was confirmed by the subcutaneous transplantation of MSCs in nude mice. Furthermore, we have detected that TAZ might increase the levels of the phosphorylation of Smad1/5/8, p38, ERK1/2, and JNK induced by BMP9. Additionally, we also found that TAZ increased the total protein level of ß-catenin induced by BMP9. In summary, our results strongly indicated that TAZ will promote the osteogenic differentiation in MSCs and MMCs induced by BMP9 through multiple signal pathways.
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Osteosarcoma (OS) is an aggressive malignant skeletal tumor characterized by an extremely poor prognosis and a high tendency to recur. The frequently used anti-OS chemotherapy regents are often limited by drug resistance and severe adverse events. It is urgent to develop more effective, tolerable and safe drugs for the treatment of OS. Andrographolide (AG), a diterpenoid lactone isolated from Andrographis paniculata, has been proved to possess anti-tumor activity against several human cancer types. In this current study, we evaluated the inhibitory effect of AG on human OS cells and probed the possible mechanism. We found that AG inhibited the proliferation of human OS cells and blocked cell cycle at G2/M phase. Furthermore, AG impeded the migration and invasion, while promoted the apoptosis of human OS cells. Moreover, we found that AG inhibited OS growth and lung metastasis in orthotopic transplantation model. Mechanistically, we demonstrated that AG suppressed the activity of Wnt/ß-catenin, PI3K/AKT and NF-κB signaling pathways. Notably, we validated that AG synergized with the inhibitors of Wnt/ß-catenin, PI3K/AKT and NF-κB to suppress the proliferation, migration and invasion of human OS cells. Collectively, our study conclusively demonstrates that AG inhibits the growth of human OS cells, thus, may be a promising candidate for the treatment of OS.