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

N. Jinawath, C. Vasoontara, K. L. Yap, M. M. Thiaville, K. Nakayama, Tian-Li Wang, Ie Ming Shih

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)1941-1948
Number of pages8
JournalOncogene
Volume28
Issue number18
DOIs
StatePublished - May 2009

Fingerprint

Stem Cell Factor
Paclitaxel
Ovarian Neoplasms
Carcinoma
Neoplasms
Proteins
Zinc Fingers
Nucleus Accumbens
Embryonic Stem Cells
Drug Resistance
Small Interfering RNA
Transcription Factors
Up-Regulation
Viruses
Phenotype
Recurrence
Cell Line

Keywords

  • Chemoresistance
  • NAC-1
  • Ovarian
  • Paclitaxel

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

NAC-1, a potential stem cell pluripotency factor, contributes to paclitaxel resistance in ovarian cancer through inactivating Gadd45 pathway. / Jinawath, N.; Vasoontara, C.; Yap, K. L.; Thiaville, M. M.; Nakayama, K.; Wang, Tian-Li; Shih, Ie Ming.

In: Oncogene, Vol. 28, No. 18, 05.2009, p. 1941-1948.

Research output: Contribution to journalArticle

Jinawath, N. ; Vasoontara, C. ; Yap, K. L. ; Thiaville, M. M. ; Nakayama, K. ; Wang, Tian-Li ; Shih, Ie Ming. / NAC-1, a potential stem cell pluripotency factor, contributes to paclitaxel resistance in ovarian cancer through inactivating Gadd45 pathway. In: Oncogene. 2009 ; Vol. 28, No. 18. pp. 1941-1948.
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