Nuclear Receptor Nur77 Facilitates Melanoma Cell Survival under Metabolic Stress by Protecting Fatty Acid Oxidation

Abstract

Fatty acid oxidation (FAO) is crucial for cells to overcome metabolic stress by providing ATP and NADPH. However, the mechanism by which FAO is regulated in tumors remains elusive. Here we show that Nur77 is required for the metabolic adaptation of melanoma cells by protecting FAO. Glucose deprivation activates ERK2 to phosphorylate and induce Nur77 translocation to the mitochondria, where Nur77 binds to TPβ, a rate-limiting enzyme in FAO. Although TPβ activity is normally inhibited by oxidation under glucose deprivation, the Nur77-TPβ association results in Nur77 self-sacrifice to protect TPβ from oxidation. FAO is therefore able to maintain NADPH and ATP levels and prevent ROS increase and cell death. The Nur77-TPβ interaction further promotes melanoma metastasis by facilitating circulating melanoma cell survival. This study demonstrates a novel regulatory function of Nur77 with linkage of the FAO-NADPH-ROS pathway during metabolic stress, suggesting Nur77 as a potential therapeutic target in melanoma.

Synthetic lethality targeting LKB1 mutant and EGFR wild type human non-small cell lung cancer cells by glucose starvation and SGLT2 inhibition

“…In this study, we provided clear evidence suggesting that in LKB1-mutant NSCLC cells, glucose starvation induces cell death via impaired AMPK activation and oxidative stress, based on the following observations: (i) ROS level is dramatically elevated in LKB1-mutant NSCLC cells under glucose starvation (Figures 4A and S4A); (ii) Antioxidant NAC is able to protect against cell death (Figures 4C and S4C) and restore AMPK activation (Figures 5G and S5G); (iii) Reconstitution of LKB1 in LKB1-mutant cells offers significant protection against cell death induced by glucose starvation, whereas deletion of LKB1 in LKB1-WT cells greatly sensitizes cell death (Figures 3 and 5). These findings are consistent with two studies showing that fatty acid oxidation, either supported by AMPK or by Nur77, is critically important to maintain redox homeostasis in cells under metabolic stress (Jeon et al, 2012;Li et al, 2018). Interestingly, it has also been reported that Nur77 negatively regulates AMPK activity through sequestering LKB1 in the nucleus, suggesting that a sophisticated regulatory network may exist to link Nur77 and AMPK with fatty acid oxidation (Zhan et al, 2012).…”

“…At present, the non-metabolizable glucose analog 2-deoxy-D-glucose (2DG) has been widely used as a mimetic of glucose starvation and as an anti-cancer therapeutic (Aft et al, 2002;Cheong et al, 2011;Oladghaffari et al, 2015). On the other hand, it has reported that, although 2DG cannot be utilized in the glycolysis, it can enter the pentose phosphate pathway (PPP) to maintain the production of a key antioxidant nicotinamide adenine dinucleotide phosphate reduced (NADPH), thus blocking glucose starvationinduced ROS generation and cell death (Jeon et al, 2012;Li et al, 2018). In this study, while 2DG alone did not cause any cell death in LKB1-mutant cells lines, it almost totally blocked cell death in H460 (Figures 4D) and A549 cells, but not in H23 cells ( Figure S4D).…”

“…In this study, we observed an obvious upshift of AMPKα band in LKB1-mutant NSCLC cell lines upon glucose starvation (Figure 5A), suggesting that AMPKα undergo certain PTMs. Previous studies have shown that increased ROS can inhibit protein functions through direct cysteine oxidation (Anastasiou et al, 2011;Li et al, 2018). We therefore analyzed whether AMPKα undergoes oxidation upon glucose starvation.…”

“…The LKB1-AMPK axis inhibits the mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) and activates autophagy via multiple pathways (Egan et al, 2011;Gwinn et al, 2008;Inoki et al, 2003;Kim et al, 2013;Kim et al, 2011). Moreover, AMPK phosphorylates and inactivates acetyl-CoA carboxylase (ACC) to inhibit fatty acid synthesis and promote fatty acid oxidation, therefore maintaining ATP and NADPH levels (Jeon et al, 2012;Li et al, 2018;Munday et al, 1988). Among many types of cancers involving LKB1, the implication of LKB1 in NSCLC appears to be particularly important.…”

Nur77-activated lncRNA WFDC21P attenuates hepatocarcinogenesis via modulating glycolysis

“…Orphan nuclear receptor Nur77, also known as TR3 or NGFI-B, is encoded by the immediate early gene Nr4a1 and plays paradoxical roles in the development of many cancers, including HCC [14][15][16][17]. As a transcriptional factor, Nur77 could exert its biological functions through regulating the expression of its downstream targets [18].…”