Targeting Nur77 translocation.
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.
Zhang
Xiao-kun
XK
Burnham Institute for Medical Research, Cancer Center, 10901 N. Torrey Pines Road, La Jolla, CA 92037, USA. xzhang@burnham.org
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002467:Cell Nucleus / Q000378:metabolism; D002470:Cell Survival / Q000502:physiology; D004268:DNA-Binding Proteins / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D008928:Mitochondria / Q000378:metabolism; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D021381:Protein Transport; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000187:drug effects / Q000378:metabolism*; D011987:Receptors, Steroid / Q000187:drug effects / Q000378:metabolism*; D047488:Retinoid X Receptors / Q000378:metabolism; D012176:Retinoids / Q000494:pharmacology; D014157:Transcription Factors / Q000187:drug effects / Q000378:metabolism*
C099555:CD 437; D004268:DNA-Binding Proteins; C539821:NR4A1 protein, human; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D019253:Proto-Oncogene Proteins c-bcl-2; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D047488:Retinoid X Receptors; D012176:Retinoids; D014157:Transcription Factors