Munoz J L, Rodriguez-Cruz V, Greco S J, Ramkissoon S H, Ligon K L, Rameshwar P
1] Rutgers-Graduate School of Biomedical Science, Newark, NJ, USA [2] Department of Medicine, Hematology/Oncology, New Jersey Medical School, Rutgers School of Biomedical Health Sciences, Newark, NJ, USA.
Department of Medicine, Hematology/Oncology, New Jersey Medical School, Rutgers School of Biomedical Health Sciences, Newark, NJ, USA.
Cell Death Dis. 2014 Mar 27;5(3):e1145. doi: 10.1038/cddis.2014.111.
Glioblastoma Multiforme (GBM) is an aggressive adult primary brain tumor with poor prognosis. GBM patients develop resistance to the frontline chemotherapy, temozolomide (TMZ). As the connexins (Cx) have been shown to have a complex role in GBM, we investigated the role of Cx43 in TMZ resistance. Cx43 was increased in the TMZ-resistant low passage and cell lines. This correlated with the data in The Cancer Genome Atlas. Cx43 knockdown, reporter gene assays, chromatin immunoprecipitation assay, real-time PCR and western blots verified a role for Cx43 in TMZ resistance. This occurred by TMZ-resistant GBM cells being able to activate epidermal growth factor receptor (EGFR). In turn, EGFR activated the JNK-ERK1/2-AP-1 axis to induce Cx43. The increased Cx43 was functional as indicated by gap junctional intercellular communication among the resistant GBM cells. Cell therapy could be a potential method to deliver drugs, such as anti-EGF to tumor cells. Similar strategies could be used to reverse the expression of Cx43 to sensitize GBM cells to TMZ. The studies showed the potential for targeting EGF in immune therapy. These agents can be used in conjunction with stem cell therapy to treat GBM.
多形性胶质母细胞瘤（GBM）是一种侵袭性的成人原发性脑肿瘤，预后较差。GBM患者会对一线化疗药物替莫唑胺（TMZ）产生耐药性。由于连接蛋白（Cx）已被证明在GBM中具有复杂作用，我们研究了Cx43在TMZ耐药中的作用。在TMZ耐药的低传代细胞和细胞系中，Cx43表达增加。这与癌症基因组图谱中的数据相关。Cx43基因敲低、报告基因检测、染色质免疫沉淀检测、实时PCR和蛋白质印迹证实了Cx43在TMZ耐药中的作用。这是由于TMZ耐药的GBM细胞能够激活表皮生长因子受体（EGFR）。反过来，EGFR激活JNK-ERK1/2-AP-1轴以诱导Cx43表达。如耐药GBM细胞间的缝隙连接细胞间通讯所示，增加的Cx43具有功能活性。细胞疗法可能是一种向肿瘤细胞递送药物（如抗EGF）的潜在方法。类似的策略可用于逆转Cx43的表达，使GBM细胞对TMZ敏感。这些研究显示了在免疫治疗中靶向EGF的潜力。这些药物可与干细胞疗法联合用于治疗GBM。
