Curcumin Inhibits Hypoxia-Inducible Factor-1 by Degrading Aryl Hydrocarbon Receptor Nuclear Translocator: A Mechanism of Tumor Growth Inhibition

Abstract

Hypoxia-inducible factor-1 (HIF-1), a transcription factor composed of HIF-1␣ and aryl hydrocarbon receptor nuclear translocator (ARNT), plays a key role in cell survival and angiogenesis in hypoxic tumors, and many efforts have been made to develop anticancer agents that target HIF-1␣. However, although ARNT is also required for HIF-1 activity, ARNT has been disregarded as a therapeutic target. Curcumin is a commonly used spice and coloring agent with a variety of beneficial biological effects, which include tumor inhibition. In the present study, we tested the possibility that curcumin inhibits tumor growth by targeting HIF-1. The effects of curcumin on HIF-1 activity and expression were examined in cancer cell lines and in xenografted tumors. We found that curcumin inhibits HIF-1 activity and that this in turn down-regulates genes targeted by HIF-1. Moreover, of the two HIF-1 subunits, only ARNT was found to be destabilized by curcumin in several cancer cell types, and furthermore, ARNT expression rescued HIF-1 repression by curcumin. We also found that curcumin stimulated the proteasomal degradation of ARNT via oxidation and ubiquitination processes. In mice bearing Hep3B hepatoma, curcumin retarded tumor growth and suppressed ARNT, erythropoietin, and vascular endothelial growth factor in tumors. These results suggest that the anticancer activity of curcumin is attributable to HIF-1 inactivation by ARNT degradation.

Aryl hydrocarbon receptor nuclear translocator in human liver is regulated by miR-24

“…In contrast, ARNT mRNA was not affected by these treatments (Choi et al, 2006), indicating the possibility of post-transcriptional regulation.…”

“…It has been reported that the ARNT protein level was decreased by H 2 O 2 or ROS in human cell lines (Choi et al, 2006(Choi et al, , 2008. In contrast, ARNT mRNA was not affected by these treatments (Choi et al, 2006), indicating the possibility of post-transcriptional regulation.…”

Development and characterization of co-loaded curcumin/triazole-halloysite systems and evaluation of their potential anticancer activity

“…Several studies, also, report that it is an agent possessing a wide variety of biological and pharmacological activities, including anti-proliferation (Choi et al, 2006), antiapoptosis (Aggarwal et al, 2008), anti-angiogenesis (Lin et al, 2007) and inhibition of cell invasion and metastasis (Chen et al, 2008).…”

EF24, a novel curcumin analog, disrupts the microtubule cytoskeleton and inhibits HIF-1

“…13,14 However, EF24 is not only significantly more active than curcumin, but it also inhibits HIF-1 via a totally distinct mechanism. We found that curcumin inhibited HIF-1α transcription only at the highest concentration examined (50-100 μM), whereas EF24 downregulated HIF-1α in a dose-dependent manner at low, sublethal concentrations.…”

“…12 In this study, we set out to elucidate aspects of the molecular mechanism of action of EF24. We focused on the reported antiangiogenic activities of curcumin, partially mediated by inhibition of the hypoxia-inducible factor (HIF-1) pathway 13,14 and determined whether EF24 had an effect on the HIF pathway.…”