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NAC-1, a potential stem cell pluripotency factor, contributes to paclitaxel resistance in ovarian cancer through inactivating Gadd45 pathway

Oncogene volume 28, pages 1941–1948 (2009)Cite this article

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-γ-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 Gadd45γ, which interacted with Gadd45gip1. Reducing Gadd45γ 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.

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Acknowledgements

This work is in memory of Ms Sean Patrick, the founder of HERA women's cancer foundation who has fought courageously with recurrent ovarian cancer. The authors appreciate the valuable comments from members in our laboratory. This work is supported by NIH RO1CA103937 (IMS), NIH RO1CA129080 (IMS) and the HERA women's cancer foundation OSB1 (NJ, USA).

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Authors and Affiliations

  1. Departments of Pathology, Oncology, and Gynecology and Obstetrics, Johns Hopkins Medical Institutions, Baltimore, MD, USA

    N Jinawath, C Vasoontara, K-L Yap, M M Thiaville, T-L Wang & I-M Shih

  2. Department of Gynecology and Obstetrics, Shimane University, Izumo, Japan

    K Nakayama

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  1. N Jinawath
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  2. C Vasoontara
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Correspondence to I-M Shih.

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Jinawath, N., Vasoontara, C., Yap, KL. et al. NAC-1, a potential stem cell pluripotency factor, contributes to paclitaxel resistance in ovarian cancer through inactivating Gadd45 pathway. Oncogene 28, 1941–1948 (2009). https://doi.org/10.1038/onc.2009.37

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