RESUMO
BACKGROUND: Glioblastoma (GBM) is the most common and most aggressive form of brain cancer. After surgery, radiotherapy is the mainstay of treatment for GBM patients. Unfortunately, the vast majority of GBM patients fail responding to radiotherapy because GBM cells remain highly resistant to radiation. Radiotherapy-induced DNA damage response may correlate with therapeutic resistance. METHODS: Ionizing radiation (IR) was used to induce DNA damage. Cell proliferation and migration were detected by wound-healing, MTT and apoptosis assays. Dual-luciferase assays and Western blot analysis were performed to evaluate NF-κB activation and validate microRNA targets. Real-time PCR was used to study mRNA and microRNA levels. RESULTS: IR-induced DNA damage activated NF-κB in GBM cells which promoted expression of IL-6, IL-8 and Bcl-xL, thereby contributing to cell survival and invasion. Knockdown SENP2 expression enhanced NF-κB essential modulator (NEMO) SUMOylation and NF-κB activity following IR exposure. miR-181b targets SENP2 and positively regulated NF-κB activity. CONCLUSION: NF-κB activation by DNA damage in GBM cells confers resistance to radiation-induced death.
Assuntos
Neoplasias Encefálicas/genética , Cisteína Endopeptidases/metabolismo , Glioblastoma/genética , MicroRNAs/biossíntese , Apoptose/efeitos da radiação , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/radioterapia , Linhagem Celular Tumoral , Movimento Celular/efeitos da radiação , Proliferação de Células/efeitos da radiação , Sobrevivência Celular/efeitos da radiação , Cisteína Endopeptidases/genética , Dano ao DNA/genética , Dano ao DNA/efeitos da radiação , Regulação Neoplásica da Expressão Gênica , Glioblastoma/patologia , Glioblastoma/radioterapia , Humanos , MicroRNAs/metabolismo , NF-kappa B/genética , Radiação Ionizante , Transdução de Sinais/genética , Transdução de Sinais/efeitos da radiaçãoRESUMO
ß-Elemene, an active component of herb medicine Curcuma wenyujin, has been shown to antagonize glioblastoma cells by inducing apoptosis. However, how ß-elemene induces apoptosis of these cells remains unclear. In this study, we report that ß-elemene disrupted the formation of the Hsp90/Raf-1 complex, a key step in maintaining the conformation stability of Raf-1, and caused deactivation of Raf-1 and inhibition of the ERK pathway, thereby leading to apoptosis of glioblastoma cells. Specifically, treatment of glioblastoma cell lines with ß-elemene attenuated phosphorylation of multiple members of the kinase families in the Ras/Raf/MEK/ERK cascade, including Raf-1 and ERK as well as downstream signaling targets such as Bcl-2. These results suggest that the Hsp90/Raf-1 complex could be a promising molecular target for new drug development for the treatment of glioblastoma.