Targeting the nuclear orphan receptor NR4A1: a key target in lung cancer progression and therapeutic resistance

Abstract

As a malignant tumor with high morbidity and mortality, lung cancer is associated with a variety of risk factors, including smoking, exposure to occupational carcinogens, familial inheritance, and chronic lung disease. Lung cancer is often detected late and has a complex pathogenesis, so early diagnosis and intervention of lung cancer are essential. Finding effective targets is important to develop new treatments for lung cancer. As a member of Group 4A of the nuclear receptor subfamily, Nuclear Receptor Subfamily 4 Group A Member 1 (NR4A1) is an immediate early gene that encodes a transcription factor that plays a regulatory role when the cell and tissue microenvironment changes. NR4A1 plays a pro-cancer role in solid tumors including lung cancer, but a tumor suppressor role in hematological malignancies. NR4A1 palys a role through multiple mechanisms in lung cancer, including promoting cell proliferation by forming a complex with p300/specific protein 1 (Sp1) and acting on the survivin and AMP-activated protein kinase (AMPK)/mechanistic Target of Rapamycin Complex 1 (mTORC1) pathways, promoting metastasis and invasion by inducing the occurrence of transforming growth factor-β (TGF-β) dependent epithelial-mesenchymal transition (EMT), promoting vascular remodeling by acting on vascular endothelial growth factor A (VEGF-A), promoting immune escape by acting on programmed cell death-1 (PD-1) dependent T cell exhaustion, promoting cell apoptosis interacted with B-cell lymphoma-2 (Bcl-2) and promoting metabolic reprogramming by increasing fatty acid oxidation. In recent years, several studies on NR4A1-related agonists and inhibitors in lung cancer have been reported. These compounds are expected to become drugs for targeted tumor therapy, but current research is limited to cellular and animal experiments. It still takes time to verify and evaluate clinical applications, other biological effects and potential side effects. This review summarizes the biological role of NR4A1 in lung cancer and describes the molecular mechanisms and signaling pathways regulated by NR4A1. This paper will provide a theoretical basis for the early treatment of lung cancer by using NR4A1-related compounds in the clinic.

Keywords: DIM-C-pPhOH; NR4A1; cytosporone B; lung cancer; molecular mechanism; signaling pathways.

Figure 1

A NR4A1 structure and functional domains schematic. Structure of NR4A1 including DNA-binding domain (DBD), C-terminal ligand-binding domain (LBD), hinge region (Hinge), and N-terminal trans-activating domain (TAD). The DBD region interacts specifically with the DNA sequences of the NBRE and the NurRE. NR4A1 forms a heterodimer with the retinoid X receptor (RXR), which then binds to the DR5 response element to produce transcriptional activation. NR4A1 forms DNA-binding complexes with Sp1 and p300 to exert transcriptional.

Figure 2

Role of NR4A1 in different tissues. (A) NR4A1 plays a tumor-promoting role in lung, breast, colorectal, pancreatic, melanoma, and bladder cancers. NR4A1 exerts an inhibitory effect in acute myeloid leukemia and myeloproliferative diseases. (B) NR4A1 expression is normal or low in tissues of healthy individuals and in tissue adjacent to the tumor in lung cancer patients, but NR4A1 is overexpressed in cancerous tissues.

Figure 3

Role and molecular mechanism of NR4A1 in the pathogenesis of lung cancer. (A) The role of NR4A1 in lung cancer cell proliferation. The NR4A1/Sp1/p300 complex upregulates survivin; NR4A1 inhibits p53 acetylation, which in turn induces activation of the AMPK/mTORC1 pathway. (B) The role of NR4A1 in lung cancer cell migration and invasion. The NR4A1/Sp1 complex promotes G9A expression; NR4A1 export from the nucleus is induced by phosphorylation of the TGF-β/TGF-β receptor. (C) The role of NR4A1 in immunomodulation. The NR4A1/AP-1 complex decreases tumor cell killing by T cells by reducing IFN-γ and IL-2 secretion. (D) The role of NR4A1 in apoptosis of lung cancer cells. Nuclear export of NR4A1 indirectly induces apoptosis by NR4A1 binding to mitochondrial Bcl-2. (E) The role of NR4A1 in lung cancer cell metabolism. (F) The pro-angiogenic role of NR4A1 in lung cancer cells. VEGF-A binding to VEGF-A receptor 2 upregulates NR4A1 expression and participates in angiogenesis.