RESUMO
In spite of numerous advances, the 5-year survival rate for head and neck squamous cell cancer has remained largely stagnant and few new anti-tumor drugs have been developed. PCH4, a derivative of n-butylidenephthalide, has been investigated for its anti-tumor effects on oral squamous cell carcinoma (OSCC). The aim of this study was to investigate the anti-tumor mechanism of a potential target gene, Nur77, in OSCC cells, which can be induced by PCH4 treatment. Data show that PCH4 promoted Nur77 translocation from the nucleus to the cytoplasm and induced cell apoptosis in OSCC cells. When Nur77 translocation was blocked, the degree of tumor apoptosis caused by PCH4 was significantly inhibited (p < 0.05). Within the MAPK pathway, PCH4 only induced JNK phosphorylation. Furthermore, treatment with a JNK inhibitor significantly reduced PCH4-induced apoptosis (p < 0.05) and decreased PCH4-induced Nur77 expression (p < 0.05). In a xenograft animal model, administration of PCH4 also showed anti-tumor effects. We have demonstrated that OSCC cells are sensitive to PCH4 and that Nur77 protein translocation from the nucleus to the cytoplasm might be associated with the induction of apoptosis by PCH4. These results indicate that PCH4 may serve as a potential anti-tumor drug for OSCC therapy.
Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Benzofuranos/farmacologia , Carcinoma de Células Escamosas/tratamento farmacológico , Proliferação de Células/efeitos dos fármacos , Etilaminas/farmacologia , Neoplasias Bucais/tratamento farmacológico , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/metabolismo , Anidridos Ftálicos/farmacologia , Transporte Ativo do Núcleo Celular , Animais , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Feminino , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias Bucais/genética , Neoplasias Bucais/metabolismo , Neoplasias Bucais/patologia , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/genética , Fosforilação , Inibidores de Proteínas Quinases/farmacologia , RNA Mensageiro/metabolismo , Fatores de Tempo , Carga Tumoral/efeitos dos fármacos , Regulação para Cima , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Lung cancer is the leading cause of cancer mortality worldwide and tumor metastasis is the major cause of cancer-related death. Our previous study suggested that Homeobox A5 (HOXA5) could inhibit lung cancer cell invasion via regulating cytoskeletal remodeling and involved in tumor metastasis. Recently, consensus HOX binding sites was found in the p53 gene promoter region. However, whether the HOXA5 could cooperate with p53 and contribute the inhibition of lung cancer cell invasion is still unclear. The aim of the current study is to elucidate the correlation of HOXA5 and p53 in tumor invasion and its prognostic influence in lung cancer patient specimens. Totally 71 cases of primary non-small cell lung cancer (NSCLC) were collected. The median follow-up period is 6.8 years. Immunohistochemical stain for p53 and HOXA5 were performed. Kaplan-Meier plot was done for overall survival analysis. In addition, lung cancer cell lines transfected with wild-type or mutated p53 constructs were overexpressed with HOXA5 for invasion assay. In human specimens, HOXA5 expressed mainly in the cytoplasm (54.1%) rather than nuclei (14.6%) of the NSCLC tumor part. The HOXA5 expression is higher in adenocarcinoma than in squamous cell carcinoma (P < 0.001). In addition, poor prognosis is seen in group with both non-immunoreactive for p53 and HOXA5. HOXA5 and p53 could cooperate to inhibit tumor cell invasion significantly partly by decreasing MMP2 activity in a concentration-dependent manner. Our studies provide new insights into how HOXA5 and p53 cooperate to contribute to the suppression of lung cancer cell invasion and play good prognostic roles in NSCLC.
RESUMO
BACKGROUND: Dimethyl sulfoxide (DMSO) is an amphipathic molecule that displays a diversity of antitumor activities. Previous studies have demonstrated that DMSO can modulate AP-1 activity and lead to cell cycle arrest at the G1 phase. HLJ1 is a newly identified tumor and invasion suppressor that inhibits tumorigenesis and cancer metastasis. Its transcriptional activity is regulated by the transcription factor AP-1. However, the effects of DMSO on HLJ1 are still unknown. In the present study, we investigate the antitumor effects of DMSO through HLJ1 induction and demonstrate the mechanisms involved. METHODS AND FINDINGS: Low-HLJ1-expressing highly invasive CL1-5 lung adenocarcinoma cells were treated with various concentrations of DMSO. We found that DMSO can significantly inhibit cancer cell invasion, migration, proliferation, and colony formation capabilities through upregulation of HLJ1 in a concentration-dependent manner, whereas ethanol has no effect. In addition, the HLJ1 promoter and enhancer reporter assay revealed that DMSO transcriptionally upregulates HLJ1 expression through an AP-1 site within the HLJ1 enhancer. The AP-1 subfamily members JunD and JunB were significantly upregulated by DMSO in a concentration-dependent manner. Furthermore, pretreatment with DMSO led to a significant increase in the percentage of UV-induced apoptotic cells. CONCLUSIONS: Our results suggest that DMSO may be an important stimulator of the tumor suppressor protein HLJ1 through AP-1 activation in highly invasive lung adenocarcinoma cells. Targeted induction of HLJ1 represents a promising approach for cancer therapy, which also implied that DMSO may serve as a potential lead compound or coordinated ligand for the development of novel anticancer drugs.