Targeting Nur77 translocation

Abstract

The ultimate growth of a tumour depends on not only the rate of tumour cell proliferation, but also the rate of tumour cell death (apoptosis). Nur77 (also known as TR3 or NGFI-B), an orphan member of the nuclear receptor superfamily, controls both survival and death of cancer cells. A wealth of recent experimental data demonstrates that the Nur77 activities are regulated through its subcellular localisation. In the nucleus, Nur77 functions as an oncogenic survival factor, promoting cancer cell growth. In contrast, it is a potent killer when migrating to mitochondria, where it binds to Bcl-2 and converts its survival phenotype, triggering cytochrome c release and apoptosis. Agents, such as 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalene carboxylic acid (AHPN/CD437), which induce Nur77 migration from the nucleus to mitochondria, effectively induce apoptosis of cancer cells. Moreover, Nur77 translocation is highly controlled by retinoid X receptor (RXR), suggesting a role of RXR ligands in regulating the process. Thus, translocation of Nur77 from the nucleus to mitochondria represents a new paradigm in cancer cell apoptosis, and targeting the Nur77 translocation by AHPN/CD437 or RXR ligands promises to effectively restrict cancer cell growth by simultaneously promoting cancer cell death and suppressing cancer cell proliferation.

Keywords::

• AHPN
• apoptosis
• Bcl-2
• CD437
• mitochondria
• Nur77
• retinoid X receptor
• TR3

Acknowledgements

This work is, in part, supported by grants to X-K Zhang from the National Institutes of Health (CA87000, CA107039, GM60544, CA109345), the Susan G Komen breast cancer foundation, the US Army Medical Research and Material Command, the California Tobacco-Related Diseases research program and the California Breast Cancer Research Program.