RESUMO
BACKGROUND/AIM: Oral squamous cell carcinoma (OSCC), a major malignancy in Taiwan, is an invasive epithelial neoplasm resulting in a low survival rate. Current treatments do not prevent OSCC progression, and antitumor therapies should be improved. Plumbagin, a natural compound extracted from Plumbago zeylanica L., appears to have antitumor effects in various tumors. The antitumor mechanism of plumbagin in OSCC is still unclear. This study investigated the molecular mechanism through which plumbagin induces apoptosis. MATERIALS AND METHODS: To investigate the antiproliferative and pro-apoptotic effects of Plumbagin on OSCC cells and explore its underlying mechanism, cell counting kit-8, cell cycle analysis, and annexin V/PI assay were conducted. The functions of plumbagin on endoplasmic reticulum (ER) stress, reactive oxygen species (ROS) production, and mitochondrial membrane potential (MMP) deficiency were analyzed using flow cytometric analysis. Plumbagin-induced apoptosis-associated proteins were detected using western blotting. RESULTS: Plumbagin induced apoptosis in OSCC cells by suppressing tumor cell proliferation through ROS production, ER stress, mitochondrial dysfunction, and caspases activation. CONCLUSION: Plumbagin is a promising antitumor candidate targeting human OSCC.
Assuntos
Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , Neoplasias Bucais , Naftoquinonas , Humanos , Espécies Reativas de Oxigênio/metabolismo , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/patologia , Neoplasias Bucais/tratamento farmacológico , Neoplasias Bucais/patologia , Carcinoma de Células Escamosas de Cabeça e Pescoço , Linhagem Celular Tumoral , Apoptose , Proliferação de Células , Estresse do Retículo EndoplasmáticoRESUMO
Osteosarcoma is the most common bone malignancy that occurs in the young population. After osteosarcoma cells metastasize to the lung, prognosis is very poor owing to difficulties in early diagnosis and effective treatment. Recently, connective tissue growth factor (CTGF) was reported to be a critical contributor to osteosarcoma metastasis. However, the detailed mechanism associated with CTGF-directed migration in bone neoplasms is still mostly unknown. Through the in vivo and in vitro examination of osteosarcoma cells, this study suggests that VCAM-1 up-regulation and increased osteosarcoma cell migration are involved in this process. Antagonizing αvß3 integrin inhibited cell migration. Moreover, FAK, PI3K, Akt and NF-κB activation were also shown to be involved in CTGF-mediated osteosarcoma metastasis. Taken together, CTGF promotes VCAM-1 production and further induces osteosarcoma metastasis via the αvß3 integrin/FAK/PI3K/Akt/NF-κB signaling pathway, which could represent a promising clinical target to improve patient outcome.
Assuntos
Neoplasias Ósseas/metabolismo , Movimento Celular/fisiologia , Fator de Crescimento do Tecido Conjuntivo/toxicidade , Osteossarcoma/metabolismo , Regulação para Cima/fisiologia , Molécula 1 de Adesão de Célula Vascular/biossíntese , Animais , Neoplasias Ósseas/induzido quimicamente , Neoplasias Ósseas/genética , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Camundongos , Camundongos SCID , Osteossarcoma/induzido quimicamente , Osteossarcoma/genética , Regulação para Cima/efeitos dos fármacos , Molécula 1 de Adesão de Célula Vascular/genéticaRESUMO
Osteosarcoma is the most common primary bone tumor in children and teens. The exact molecular mechanism underlying osteosarcoma progression still remains unclear. The CX3CL1/fractalkine has been implicated in various tumors but not in osteosarcoma. This study is the first to show that fractalkine promotes osteosarcoma metastasis by promoting cell migration. Fractalkine expression was higher in osteosarcoma cell lines than in normal osteoblasts. Fractalkine induced cell migration by upregulating intercellular adhesion molecule-1 (ICAM-1) expression via CX3CR1/PI3K/Akt/NF-κB pathway in human osteosarcoma cells. Knockdown of fractalkine expression markedly inhibited cell migration and lung metastasis in osteosarcoma. Finally, we showed a clinical correlation between CX3CL1 expression and ICAM-1 expression as well as tumor stage in human osteosarcoma tissues. In conclusion, our results indicate that fractalkine promotes cell migration and metastasis of osteosarcoma by upregulating ICAM-1 expression. Thus, fractalkine could serve a novel therapeutic target for preventing osteosarcoma metastasis.
RESUMO
Osteosarcoma is a common, high malignant, and metastatic bone cancer. Amphiregulin (AREG) has been associated with cancer cellular activities. However, the effect of AREG on metastasis activity in human osteosarcoma cells has yet to be determined. We determined that AREG increases the expression of intercellular adhesion molecule-1 (ICAM-1) through PI3K/Akt signaling pathway via its interaction with the epidermal growth factor receptor, thus resulting in the enhanced cell migration of osteosarcoma. Furthermore, AREG stimulation increased the association of NF-κB to ICAM-1 promoter which then up-regulated ICAM-1 expression. Finally, we observed that shRNA silencing of AREG decreased osteosarcoma metastasis in vivo. Our findings revealed a relationship between osteosarcoma metastatic potential and AREG expression and the modulating effect of AREG on ICAM-1 expression.
Assuntos
Neoplasias Ósseas/patologia , Família de Proteínas EGF/metabolismo , Molécula 1 de Adesão Intercelular/metabolismo , Neoplasias Pulmonares/secundário , Osteossarcoma/patologia , Anfirregulina , Animais , Apoptose , Western Blotting , Neoplasias Ósseas/genética , Neoplasias Ósseas/metabolismo , Movimento Celular , Proliferação de Células , Imunoprecipitação da Cromatina , Família de Proteínas EGF/genética , Receptores ErbB/genética , Receptores ErbB/metabolismo , Humanos , Técnicas Imunoenzimáticas , Molécula 1 de Adesão Intercelular/química , Molécula 1 de Adesão Intercelular/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Masculino , Camundongos , Camundongos SCID , NF-kappa B/genética , NF-kappa B/metabolismo , Osteossarcoma/genética , Osteossarcoma/metabolismo , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , RNA Mensageiro/genética , RNA Interferente Pequeno/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Osteosarcoma (OS) is a primary malignant tumor of bone and is most prevalent in children and adolescents. OS is frequently associated with pulmonary metastasis, which is the main cause of OS-related mortality. OS has a poor prognosis and is often unresponsive to conventional chemotherapy. In this study, we determined that Nimbolide, a novel anti-cancer therapy, acts by modulating multiple mechanisms in osteosarcoma cells. Nimbolide induces apoptosis by increasing endoplasmic reticulum (ER) stress, mitochondrial dysfunction, accumulation of reactive oxygen species (ROS), and finally, caspase activation. We also determined that Nimbolide inhibits cell migration, which is crucial for metastasis, by reducing the expression of integrin αvß5. In addition, our results demonstrate that integrin αvß5 expression is modulated by the PI3K/Akt and NF-κB signaling cascade. Nimbolide has potential as an anti-tumor drug given its multifunctional effects in OS. Collectively, these results help us to understand the mechanisms of action of Nimbolide and will aid in the development of effective therapies for OS.
