Nucleus accumbens-1/GADD45GIP1 axis mediates cisplatin resistance through cellular senescence in ovarian cancer.

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.