Department of Neurosurgery, Mackay Memorial Hospital Taipei, Taiwan ; Graduate Institute of Injury Prevention and Control, Taipei Medical University Taipei, Taiwan.
Front Oncol. 2013 Mar 4;3:43. doi: 10.3389/fonc.2013.00043. eCollection 2013.
Tumor suppressor p53 are frequently mutated in glioblastomas (GBMs) and appears to contribute, in part, to resistance to temozolomide (TMZ) and therapeutic drugs. WW domain-containing oxidoreductase WWOX (FOR or WOX1) is a proapoptotic protein and is considered as a tumor suppressor. Loss of WWOX gene expression is frequently seen in malignant cancer cells due to promoter hypermethylation, genetic alterations, and translational blockade. Intriguingly, ectopic expression of wild type WWOX preferentially induces apoptosis in human glioblastoma cells harboring mutant p53. WWOX is known to physically bind and stabilize wild type p53. Here, we provide an overview for the updated knowledge in p53 and WWOX, and postulate potential scenarios that wild type and mutant p53, or isoforms, modulate the apoptotic function of WWOX. We propose that triggering WWOX activation by therapeutic drugs under p53 functional deficiency is needed to overcome TMZ resistance and induce GBM cell death.
抑癌基因 p53 在胶质母细胞瘤（GBM）中经常发生突变，似乎部分导致了对替莫唑胺（TMZ）和治疗药物的耐药性。WW 结构域包含氧化还原酶 WWOX（FOR 或 WOX1）是一种促凋亡蛋白，被认为是一种肿瘤抑制因子。由于启动子过度甲基化、遗传改变和翻译阻断，WWOX 基因表达的缺失在恶性癌细胞中经常发生。有趣的是，野生型 WWOX 的异位表达优先诱导携带突变型 p53 的人胶质母细胞瘤细胞凋亡。已知 WWOX 与野生型 p53 物理结合并稳定其表达。在这里，我们概述了 p53 和 WWOX 的最新知识，并提出了野生型和突变型 p53 或同工型可能调节 WWOX 凋亡功能的潜在情况。我们提出，在 p53 功能缺陷的情况下，通过治疗药物触发 WWOX 的激活对于克服 TMZ 耐药性和诱导 GBM 细胞死亡是必要的。
