Role and regulation of NUR77 in hypoxic tumor microenvironment and ferroptotic tumor cell death

Abstract

Hypoxia is a common characteristic in the tumor microenvironment (TME) and a critical stimulant of primary and metastatic colorectal cancer (CRC) growth and progression. Orphan nuclear receptor Nur77 (NR4A1) is frequently overexpressed in hypoxic CRC tissues and cell lines. In Chapter 3, Nur77 is shown to regulate Dicer-mediated microRNA biogenesis that explain its pronounced tumor-promoting activities in CRC cells under hypoxic conditions. Mechanistically, Nur77 repressed Dicer, a pivotal microRNA processor, and subsequently reduced the biogenesis of let-7i-5p, which targeted p110α mRNA 3’UTR and modulated p110α mRNA stability. Nur77 depletion or let-7i-5p overexpression suppressed the CRC metastasis in mouse model.

Furthermore, an inhibitory role of a natural small molecule ginsenoside compound K (CK) in CRC stemness (CSC) by targeting Nur77 in the hypoxic microenvironment is identified in Chapter 4. CK potently inhibited CSCs self-renewal in the hypoxic CRC cells, and that this was mediated through Nur77 via a p110α PIK3CA-Akt signaling pathway. Importantly, CK could effectively reduce tumorigenesis and metastasis in xenograft mice with no adverse effects on the liver, lungs, spleen, heart, and kidneys in vivo. These findings suggest that CK could be a nutraceutical with a beneficial effect against CRC through targeting CSCs. Notably, a dose-dependent enhancement of ROS was found upon CK treatment. This massive cellular oxidation and excessive lipid peroxidation by high levels of ROS is known to link an iron-dependent mode of cell death ferroptosis. In Chapter 5, a new role for CK in stimulating ferroptosis in cancer cell lines under hypoxic conditions is studied. In search of the underlying mechanisms, Nur77 bound to the Gpx4 promoter region to inhibit its transcription. Nur77 was also found to regulate SLC7A11 by protecting it from ubiquitination and proteasome degradation. Taken together, these data uncovered a novel mechanistic role of Nur77-PI3K/Akt signaling in CRC metastasis under hypoxia. CK could be exploited further as a therapeutic strategy for CRC patients.