van der Wijst Monique G P, Brown Robert, Rots Marianne G
Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands.
Department of Surgery and Cancer, Imperial College London, UK.
Biochim Biophys Acta. 2014 Dec;1846(2):494-509. doi: 10.1016/j.bbcan.2014.09.004. Epub 2014 Sep 28.
Ovarian cancer is the most lethal gynecological tumor type in the world due to late stage detection, and resistance to chemotherapy. Therefore, alternative additional therapies are required. The etiology of ovarian cancer remains largely unknown, but risk factors point toward an important role for oxidative stress. Both healthy and tumor cells can cope with oxidative stress by activating the transcription factor Nrf2 (also known as Nfe2l2), the master regulator of antioxidant and cytoprotective genes. Indeed, for most ovarian cancers, aberrant activation of Nrf2 is observed, which is often associated with a copy number loss within the Nrf2-inhibitory complex KEAP1-CUL3-RBX1. A key role for Nrf2 in ovarian carcinogenesis has been validated by siRNA studies. However, to exploit the Nrf2 pathway for therapeutic interventions, potential side-effects should be minimized. In this review, we explore ovarian cancer specific factors with links to aberrant activity of Nrf2, to be exploited in future combination strategies, synergistic with direct Nrf2 inhibitory drugs. Particularly, we propose to stratify patients based on common ovarian cancer mutations (KRAS, BRAF, ERBB2, BRCA1 and its link with estradiol, TP53) for future NRF2 targeting strategies.
由于发现时已处于晚期且对化疗耐药，卵巢癌是全球最致命的妇科肿瘤类型。因此，需要其他额外的治疗方法。卵巢癌的病因在很大程度上仍然未知，但风险因素表明氧化应激起着重要作用。健康细胞和肿瘤细胞都可以通过激活转录因子Nrf2（也称为Nfe2l2）来应对氧化应激，Nrf2是抗氧化和细胞保护基因的主要调节因子。事实上，在大多数卵巢癌中都观察到Nrf2的异常激活，这通常与Nrf2抑制复合物KEAP1-CUL3-RBX1内的拷贝数缺失有关。Nrf2在卵巢癌发生中的关键作用已通过siRNA研究得到验证。然而，为了利用Nrf2途径进行治疗干预，应尽量减少潜在的副作用。在这篇综述中，我们探索与Nrf2异常活性相关的卵巢癌特异性因素，以便在未来的联合策略中加以利用，与直接的Nrf2抑制药物协同作用。特别是，我们建议根据常见的卵巢癌突变（KRAS、BRAF、ERBB2、BRCA1及其与雌二醇的联系、TP53）对患者进行分层，以便未来制定针对NRF2的治疗策略。
