Title:The Nuclear Orphan Receptors NR4A as Therapeutic Target in Cancer Therapy
Volume: 12
Issue: 9
Author(s): Alexander J. A. Deutsch, Hannes Angerer, Tamara E. Fuchs and Peter Neumeister
Affiliation:
Keywords:
6-mercaptopurine, Apoptosis, Bcl-2, Therapeutic target, Cisplatin, Mitochondrial targeting, NR4A agonist, NR4A antagonist, NR4A1, NR4A2, NR4A3, Nuclear orphan receptor, Rituximab, RXR, VP16
Abstract: NR4A1 (Nur77), NR4A2 (Nurr1) and NR4A3 (Nor-1) are three members of the orphan nuclear receptor (NR) family referred
to as NR4A family. This subgroup activates gene expression in a constitutive ligand-independent manner. These nuclear receptors are
classified as early response genes that are induced by a diverse range of signals. These orphan NRs have been implicated in cell cycle
regulation, apoptosis, inflammation, metabolism and more recently in carcinogenesis. The ultimate growth of a tumor depends not only
on the rate of tumor cell proliferation, but also the rate of apoptosis and NR4A1 controls both, survival and death of cancer cells. It has
been demonstrated that NR4A1 activities are regulated through its subcellular localisation. In the nucleus, NR4A1 can function in a
context dependent manner either as an oncogenic survival factor, promoting cancer cell growth or as the opposite through the activation
of apoptosis. Additionally, in an atypical fashion, it is a potent killer when migrating to the mitochondria, where it binds to Bcl-2 and
converts its survival phenotype, triggering cytochrome c release and apoptosis. The most convincing evidence that nuclear orphan
receptors function as critical tumor suppressors is the observation that the NR4A1 and NR4A3 double knock out mouse develops rapidly
acute myeloid leukemia. Down regulation of NR4A1 and NR4A3 was a common feature in leukemic blasts from human AML patients.
In particular, the recent identification of pro-apoptotic agents inducing NR4A expression or acting as agonists suggests that these
members could serve as potential targets for cancer therapy.
