RESUMO
Glioblastoma multiforme (GBM) is the most common type of malignant brain tumor. The present standard treatment for GBM has not been effective; therefore, the prognosis remains dramatically poor and prolonged survival after treatment is still limited. The new therapeutic strategies are urgently needed to improve the treatment efficiency. Doxorubicin (Dox) has been widely used in the treatment of many cancers for decades. In recent years, with the advancement of delivery technology, more and more research indicates that Dox has the opportunity to be used in the treatment of GBM. Amphiregulin (AREG), a ligand of the epidermal growth factor receptor (EGFR), has been reported to have oncogenic effects in many cancer cell types and is implicated in drug resistance. However, the biological function and molecular mechanism of AREG in Dox treatment of GBM are still unclear. Here, we demonstrate that knockdown of AREG can boost Dox-induced endoplasmic reticulum (ER) stress to trigger activation in both autophagy and apoptosis in GBM cells, ultimately leading to cell death. To explore the importance of AREG in the clinic, we used available bioinformatics tools and found AREG is highly expressed in GBM tumor tissues that are associated with poor survival. In addition, we also used antibody array analysis to dissect pathways that are likely to be activated by AREG. Taken together, our results revealed AREG can serve as a potential therapeutic target and a promising biomarker in GBM.
Assuntos
Anfirregulina/genética , Apoptose , Autofagia , Neoplasias Encefálicas/metabolismo , Estresse do Retículo Endoplasmático , Glioblastoma/metabolismo , Anfirregulina/metabolismo , Antineoplásicos/toxicidade , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Doxorrubicina/toxicidade , Glioblastoma/genética , Glioblastoma/patologia , Humanos , Neurônios/efeitos dos fármacos , Neurônios/metabolismoRESUMO
Oral squamous cell carcinoma (OSCC) is the most common type of oral cancer. Despite advances in surgery, radiotherapy and chemotherapy, the overall 5year survival rate of patients with OSCC has not significantly improved. In addition, the prognosis of patients with advancedstage OSCC remains poor. Therefore, it is necessary to develop novel therapeutic modalities. Vincristine (VCR), a naturally occurring vinca alkaloid, is a classical microtubuledestabilizing agent and is widely used in the treatment of a number of cancers. Despite the proven antitumor benefits of VCR treatment, one of the major reasons for the failure of treatment is drug resistance. Changes in the tumor microenvironment are responsible for crosstalk between cells, which may facilitate drug resistance in cancers; secreted proteins may promote communication between cancer cells to induce the development of resistance. To identify the secreted proteins involved in VCR resistance, conditioned media was obtained, and an antibody array was conducted to screen a comprehensive secretion profile between VCRresistant (SASVCR) and parental (SAS) OSCC cell lines. The results showed that amphiregulin (AREG) was highly expressed and secreted in SASVCR cells. Pretreatment with exogenous recombinant AREG markedly increased drug resistance against VCR in OSCC cells, as assessed by an MTT assay. Colony formation, MTT and western blot assays were performed to investigate the effects of AREG knockdown on VCR sensitivity. The results indicated that AREG expression can regulate VCR resistance in OSCC cells; overexpression of AREG increased VCR resistance in parental cells, whereas AREG knockdown decreased the VCR resistance of resistant cells. In addition, it was also demonstrated that the glycogen synthase kinase3ß pathway may be involved in AREGinduced VCR resistance. These findings may provide rationale to combine VCR with blockade of AREGrelated pathways for the effective treatment of OSCC.