1. ¹Departments of Pathology, Oncology, and Gynecology and Obstetrics, Johns Hopkins Medical Institutions, Baltimore, MD, USA
2. ²Department of Gynecology and Obstetrics, Shimane University, Izumo, Japan

Correspondence: Dr I-M Shih, Department of Pathology, Johns Hopkins Medial Institutions, CRB-II, Room 306, 1550 Orleans Street, Baltimore, MD 21231, USA. E-mail: ishih@jhmi.edu

Received 14 October 2008; Revised 18 February 2009; Accepted 19 February 2009; Published online 23 March 2009.

Abstract

Nucleus accumbens-1 (Nac1 or NAC-1) belongs to the BTB/POZ (Pox virus and Zinc finger/Bric-a-brac Tramtrack Broad complex) transcription factor family and is a novel protein that potentially participates in self-renewal and pluripotency in embryonic stem cells. In human cancer, NAC-1 is upregulated in several types of neoplasms, but particularly in recurrent chemoresistant ovarian carcinomas, suggesting a biological role for NAC-1 in the development of drug resistance in ovarian cancer. We have assessed this possibility and shown a correlation between NAC-1 expression and ex vivo paclitaxel resistance in ovarian serous carcinoma tissues and cell lines. We found that expression of Gadd45--interacting protein 1 (Gadd45gip1), a downstream target negatively regulated by NAC-1, was reduced in paclitaxel-resistant cells. Ectopic expression of NAC-1 or knockdown of Gadd45gip1 conferred paclitaxel resistance, whereas NAC-1 knockdown or ectopic expression of Gadd45gip1 increased paclitaxel sensitivity. Furthermore, silencing NAC-1 expression or disrupting NAC-1 homodimerization by a dominant negative NAC-1 protein that contained only the BTB/POZ domain induced the expression of Gadd45, which interacted with Gadd45gip1. Reducing Gadd45 expression by small hairpin RNAs partially enhanced paclitaxel resistance. Thus, this study provides new evidence that NAC-1 upregulation and homodimerization contribute to tumor recurrence by equipping ovarian cancer cells with the paclitaxel-resistant phenotype through negative regulation of the Gadd45 pathway.