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Defining Gene Functions in Tumorigenesis by Ex vivo Ablation of Floxed Alleles in Malignant Peripheral Nerve Sheath Tumor Cells
Published on: August 25, 2021
Targeting Nur77 translocation
1Burnham Institute for Medical Research, Cancer Center, 10901 N. Torrey Pines Road, La Jolla, CA 92037, USA. xzhang@burnham.org
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.
Insights
Nur77, a nuclear receptor, controls cancer cell survival and death. Inducing its migration to mitochondria triggers apoptosis, offering a new cancer treatment strategy targeting Nur77 translocation.
Area of Science:
- Molecular Biology
- Cancer Research
- Cell Biology
Background:
- Tumor growth is determined by cancer cell proliferation and death (apoptosis).
- Nur77 (TR3/NGFI-B), an orphan nuclear receptor, regulates cancer cell survival and apoptosis.
- Subcellular localization dictates Nur77's function: nuclear Nur77 promotes survival, while mitochondrial Nur77 induces apoptosis.
Purpose of the Study:
- To investigate the role of Nur77 subcellular localization in cancer cell apoptosis.
- To explore the potential of targeting Nur77 translocation for cancer therapy.
Main Methods:
- Studied Nur77 localization and its impact on cancer cell apoptosis.
- Investigated the effect of agents like AHPN/CD437 on Nur77 translocation.
- Examined the role of retinoid X receptor (RXR) in regulating Nur77 translocation.
Main Results:
- Nur77's migration from the nucleus to mitochondria triggers apoptosis by binding Bcl-2 and causing cytochrome c release.
- Agents like AHPN/CD437 effectively induce cancer cell apoptosis by promoting Nur77 translocation.
- Retinoid X receptor (RXR) plays a crucial role in controlling Nur77 translocation.
Conclusions:
- Nur77 translocation to mitochondria represents a novel mechanism for inducing cancer cell apoptosis.
- Targeting Nur77 translocation with AHPN/CD437 or RXR ligands offers a promising therapeutic strategy to inhibit cancer growth by promoting cell death and reducing proliferation.
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