Purpose:NF-kB is a transcription factor known to promote tumorigenesis. However, NF-kB is also known to be proapoptotic and may potentially function as a tumor suppressor, although such a functional role has not been extensively investigated in human cancer. Experimental Design: A dominant negative mutant of IkBa with mutations at S32A and S36A was used to inhibit the function of NF-kB in ovarian cancer cell lines. The transcription ability, tumorigenesis, apoptosis, and drug sensitivity were examined in derivative cell lines in comparison with parental cells. We also analyzed the association of nuclear expression of NF-kB p65 with patient survival in an ovarian cancer tissue array. Results: We show that NF-kB functions as a tumor suppressor in four ovarian cancer cell lines, but it functions as an oncogene in their aggressive chemoresistant isogenic variants. NF-kB can exert its pro-apoptotic or anti-apoptotic effect by activating or repressing mitogen-activated protein kinase (MAPK) phosphorylation in parental or aggressive chemoresistant variant cell lines. We also demonstrate that the nuclear accumulation of p65 in epithelial cancer tissue is associated with a good response to chemotherapy and can predict longer overall survival for patients with ovarian cancer. Conclusions: Our data provide strong evidence that NF-kB can function as a biphasic regulator either suppressing or enhancing ovarian cancer through the regulation of MAPK and cellular apoptosis.
- Received December 9, 2010.
- Revision received February 9, 2011.
- Accepted February 11, 2011.
- Copyright © 2011, American Association for Cancer Research.