Nuclear factor-erythroid 2 (Nrf2) is the transcription factor regulating multiple antioxidant proteins and phase 2 detoxifying enzymes, and plays a crucial role in the cytoprotection against oxidative stress-associated damages. However, a potential role of Nrf2 in cancer biology has been emerged recently. In our mouse xenografts study, a stable knockdown of Nrf2 in cancer cells from the colon (HCT116 and HT29) and ovary (SKOV-3) strongly suppressed tumor growth. As an underlying mechanism, it was observed that a vessel formation and vascular endothelial growth factor (VEGF) expression were suppressed in Nrf2-inhibited colon cancer tumors. Suppressive effect of Nrf2 knockdown on angiogenesis was further evidenced by the chicken embryo chorioallantoic membrane assay and endothelial tube formation assay. The subsequent mechanism studies revealed that Nrf2-inhibited HT29 cells failed to accumulate HIF-1α protein under 1% O2 hypoxia, resulting in the limitation of the expression of HIF-1α target genes for angiogenesis. Whereas, a tumor growth suppression shown in SKOV-2 cells was associated with repressed expression of ErbB2 and the consequent increase in p27. Further experimental demonstrations showed that the expression of ErbB2 is inversely related with Nrf2 in other types of cancer cell lines; therefore, the cell growth is attenuated in these Nrf2-inhibited cancer cells. Taken together, our current study suggests that a stable Nrf2 inhibition in cancer cells suppresses tumor growth through the alterations in HIF-1α and ErbB2 signaling. Hence, Nrf2 may be a promising target to control cancer cell growth and chemoresistance.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1661. doi:10.1158/1538-7445.AM2011-1661