Nakayama Kentaro, Rahman Munmun, Rahman Mohammed Tanjimur, Nakamura Kohei, Sato Emi, Katagiri Hiroshi, Ishibashi Tomoka, Ishikawa Masako, Iida Kouji, Razia Sultana, Ishikawa Noriyuki, Kyo Satoru
Department of Obstetrics and Gynecology, Shimane University School of Medicine, Izumo, Shimane 6938501, Japan.
Department of Organ Pathology, Shimane University School of Medicine, Izumo, Shimane 6938501, Japan.
Oncol Lett. 2017 Jun;13(6):4713-4719. doi: 10.3892/ol.2017.6099. Epub 2017 Apr 26.
Nucleus accumbens-1 (NAC1), a nuclear factor belonging to the bric-a-brac-tramtrack-broad complex/pox virus and zinc finger gene family, is known to serve important roles in the proliferation and growth of tumor cells, and in chemotherapy resistance. However, the underlying molecular mechanisms through which NAC1 contributes to drug resistance remain unclear. In the present study, the role of NAC1 in drug resistance in ovarian cancer was investigated. NAC1 expression was markedly negatively associated with growth arrest and DNA-damage-inducible 45γ-interacting protein 1 (GADD45GIP1) expression in ovarian cancer. Increased NAC1 expression or decreased GADD45GIP1 expression was significantly associated with decreased progression-free survival (P=0.0041). Multivariate analysis demonstrated that NAC1/GADD45GIP1 expression was an independent prognostic factor of progression-free survival (P=0.0405). It was investigated whether cellular senescence was involved in NAC1-mediated resistance to cisplatin, a commonly used chemotherapeutic drug in the treatment of ovarian cancer. Treatment with cisplatin activated cellular senescence in ovarian cancer cell lines (SKOV3 and TOV-21G cells). Furthermore, knockdown of NAC1 by RNA interference significantly increased GADD45GIP1 expression and inhibited cisplatin-induced cellular senescence, resulting in increased cisplatin cytotoxicity in SKOV3 cells, which express increased levels of NAC1. To investigate whether the sensitizing effect of NAC1 inhibition on cisplatin-induced cytotoxicity may be attributed to the suppression of cellular senescence, the effects of NAC1 overexpression were assessed in TOV-21G cells, which do not express endogenous NAC1. Transfection with NAC1 in TOV-21G cells reduced the sensitivity of TOV-21G cells to cisplatin, indicating that suppression of cellular senescence was induced by GADD45GP1 activation. The results of the present study suggest that NAC1 is a negative regulator of cellular senescence and that NAC1-dependent suppression of senescence, mediated through GADD45GIP1, serves an important role in promoting cisplatin resistance. Therefore, the NAC1/GADD45GIP1 axis may be a potential target for the treatment of ovarian cancer, particularly in platinum-resistant cancers.
伏隔核-1（NAC1）是一种属于bric-a-brac-tramtrack-broad复合体/痘病毒和锌指基因家族的核因子，已知其在肿瘤细胞的增殖和生长以及化疗耐药性中发挥重要作用。然而，NAC1导致耐药性的潜在分子机制仍不清楚。在本研究中，研究了NAC1在卵巢癌耐药中的作用。NAC1表达与卵巢癌中的生长停滞和DNA损伤诱导的45γ相互作用蛋白1（GADD45GIP1）表达显著负相关。NAC1表达增加或GADD45GIP1表达降低与无进展生存期缩短显著相关（P = 0.0041）。多变量分析表明，NAC1/GADD45GIP1表达是无进展生存期的独立预后因素（P = 0.0405）。研究了细胞衰老是否参与NAC1介导的对顺铂的耐药性，顺铂是治疗卵巢癌常用的化疗药物。顺铂处理激活了卵巢癌细胞系（SKOV3和TOV-21G细胞）中的细胞衰老。此外，通过RNA干扰敲低NAC1显著增加了GADD45GIP1表达并抑制了顺铂诱导的细胞衰老，导致SKOV3细胞中顺铂细胞毒性增加，SKOV3细胞中NAC1表达水平升高。为了研究NAC1抑制对顺铂诱导的细胞毒性的致敏作用是否可能归因于细胞衰老的抑制，在不表达内源性NAC1的TOV-21G细胞中评估了NAC1过表达的影响。在TOV-21G细胞中转染NAC1降低了TOV-21G细胞对顺铂的敏感性，表明细胞衰老的抑制是由GADD45GP1激活诱导的。本研究结果表明，NAC1是细胞衰老的负调节因子，并且通过GADD45GIP1介导的NAC1依赖性衰老抑制在促进顺铂耐药性中起重要作用。因此，NAC1/GADD45GIP1轴可能是治疗卵巢癌的潜在靶点，特别是在铂耐药癌症中。
