RESUMO
To date, the major role of HPV16E6 in cancer has been considered to be its ability to inhibit the p53 tumor-suppressor protein, thereby thwarting p53-mediated cytotoxic responses to cellular stress signals. Here, we show that HPV16E6-dependent c-fos oncogenic protein expression contributes to AP-1 complex formation under oxidative stress in SiHa cells (HPV16-positive squamous cell carcinoma of the cervix). In addition, we examined the role of HPV16E6 in TGF-α-induced c-fos expression and found that the c-fos protein expression induced by TGF-α is HPV16E6 dependent. Thus, our results provide the first evidence that HPV16E6 contributes to AP-1 complex formation after both ligand-dependent and independent EGFR activation, suggesting a new therapeutic approach to the treatment of HPV-associated tumors.
Assuntos
Proteínas Oncogênicas Virais/metabolismo , Proteínas Proto-Oncogênicas c-fos/metabolismo , Proteínas Repressoras/metabolismo , Fator de Transcrição AP-1/metabolismo , Linhagem Celular Tumoral , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Proteínas Oncogênicas Virais/genética , Proteínas Proto-Oncogênicas c-fos/genética , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Proteínas Repressoras/genética , Fator de Transcrição AP-1/genética , Fator de Crescimento Transformador alfa/metabolismo , Neoplasias do Colo do Útero/metabolismo , Neoplasias do Colo do Útero/patologia , Neoplasias do Colo do Útero/virologiaRESUMO
Inflammation is associated with disease progression and, by largely unknown mechanisms, has been said to drive oncogenesis. At inflamed sites, neutrophils deploy a potent antimicrobial arsenal that includes proteinases, antimicrobial peptides, and ROS. Reactive oxygen species (ROSs) induce chemokines. In the present study, the concentrations of IL-8 in culture supernatants of HeLa cells treated with ROS were determined by enzyme-linked immunosorbent assay. We used o-phenanthroline to deplete Fe(2+) in order to investigate the mechanisms through which ROSs induce IL-8 secretion in our system. The iron chelator o-phenanthroline effectively inhibited H(2)O(2)-induced ERK2 activation. Enzyme-linked immunosorbent assays showed that IL-8 protein secretion was elevated in ROS-treated HeLa cells. When Fe(2+) was removed from these cells, IL-8 secretion was inhibited. Collectively, these results indicate that Fe(2+)-mediated Erk pathway activation is an important signal transduction pathway in ROS-induced IL-8 secretion in epithelial cells.
Assuntos
Quimiocinas/metabolismo , Células Epiteliais/metabolismo , Regulação da Expressão Gênica , Interleucina-8/metabolismo , Ferro/metabolismo , Oxigênio/metabolismo , Anti-Infecciosos/farmacologia , Ensaio de Imunoadsorção Enzimática/métodos , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Células HeLa , Humanos , Peróxido de Hidrogênio/química , Fenantrolinas/farmacologia , Espécies Reativas de Oxigênio , Transdução de SinaisRESUMO
For decades, platinum drugs have been the mainstay of cancer treatment. However, over time, drug resistance develops, leaving few treatment options. Here we show that platelet-derived growth factor α receptor (PDGF α receptor)-mediated signaling plays a key role in hepatocyte growth factor (HGF) receptor (c-Met) upregulation, which in turn is thought to play an important role in chemotherapy resistance. PDGF α receptor inhibition eliminates cisplatin-dependent Met expression in cervical cancer cell lines. PDGF α receptor inhibitors are widely used in clinical settings, suggesting that the clinical translation of our findings could reduce the suffering of people from drug resistance.