Nuclear Receptor 4A2 (NR4A2/NURR1) Regulates Autophagy and Chemoresistance in Pancreatic Ductal Adenocarcinoma

Zarei, Mahsa; Shrestha, Rupesh; Johnson, Sneha; Zhao, Yu; Karki, Keshav; Vaziri‐Gohar, Ali; Epps, Jessica; Du, Heng; Suva, Larry J.; Safe, Stephen

doi:10.1158/2767-9764.crc-21-0073

Cited by 9 publications

(5 citation statements)

References 43 publications

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“…After 8 days, cells were washed with 1X PBS, fixed in 80% methanol, and stained with 0.03% (w/v) crystal violet for 10 minutes. The dye was extracted with 10% glacial acetic acid and absorbance was measured at 600 nm using a GloMax plate reader (Promega) [ 37 ].…”

Section: Methodsmentioning

confidence: 99%

Wild-type IDH1 inhibition enhances chemotherapy response in melanoma

Zarei

Hajihassani

Hue

et al. 2022

J Exp Clin Cancer Res

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Background Alternative treatment strategies in melanoma beyond immunotherapy and mutation-targeted therapy are urgently needed. Wild-type isocitrate dehydrogenase 1 (wtIDH1) has recently been implicated as a metabolic dependency in cancer. The enzyme protects cancer cells under metabolic stress, including nutrient limited conditions in the tumor microenvironment. Specifically, IDH1 generates NADPH to maintain redox homeostasis and produces α-ketoglutarate to support mitochondrial function through anaplerosis. Herein, the role of wtIDH1 in melanoma is further explored. Methods The expression of wtIDH1 was determined by qRT-PCR, and Western blot in melanoma cell lines and the effect of wtIDH1 on metabolic reprogramming in melanoma was interrogated by LC-MS. The impact of wtIDH1 inhibition alone and in combination with chemotherapy was determined in cell culture and mouse melanoma models. Results Melanoma patients express higher levels of the wtIDH1 enzyme compared to normal skin tissue, and elevated wtIDH1 expression portends poor patient survival. Knockdown of IDH1 by RNA interference inhibited cell proliferation and migration under low nutrient levels. Suppression of IDH1 expression in melanoma also decreased NADPH and glutathione levels, resulting in increased reactive oxygen species. An FDA-approved inhibitor of mutant IDH1, ivosidenib (AG-120), exhibited potent anti-wtIDH1 properties under low magnesium and nutrient levels, reflective of the tumor microenvironment in natura. Thus, similar findings were replicated in murine models of melanoma. In light of the impact of wtIDH1 inhibition on oxidative stress, enzyme blockade was synergistic with conventional anti-melanoma chemotherapy in pre-clinical models. Conclusions These results demonstrate the clinical potential of wtIDH1 inhibition as a novel and readily available combination treatment strategy for patients with advanced and refractory melanoma. Graphical Abstract Schematic shows increased wild-type IDH1 expression and activity as an adaptive response to metabolic stress induced by chemotherapy.

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Section: Methodsmentioning

confidence: 99%

Wild-type IDH1 inhibition enhances chemotherapy response in melanoma

Zarei

Hajihassani

Hue

et al. 2022

J Exp Clin Cancer Res

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“…NURR1 is also implicated in some non-neural pathologies such as several cancers [48][49][50] atherosclerosis [51], and inflammation [52]. In cancer, NURR1 can promote or suppress malignant progression depending on the cellular context.…”

Section: Nurr1 In Pathologymentioning

confidence: 99%

Mechanisms of NURR1 Regulation: Consequences for Its Biological Activity and Involvement in Pathology

García-Yagüe

Cuadrado

2023

IJMS

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NURR1 (Nuclear receptor-related 1 protein or NR4A2) is a nuclear protein receptor transcription factor with an essential role in the development, regulation, and maintenance of dopaminergic neurons and mediates the response to stressful stimuli during the perinatal period in mammalian brain development. The dysregulation of NURR1 activity may play a role in various diseases, including the onset and progression of neurodegenerative diseases, and several other pathologies. NURR1 is regulated by multiple mechanisms, among which phosphorylation by kinases or SUMOylation are the best characterized. Both post-translational modifications can regulate the activity of NURR1, affecting its stability and transcriptional activity. Other non-post-translational regulatory mechanisms include changes in its subcellular distribution or interaction with other protein partners by heterodimerization, also affecting its transcription activity. Here, we summarize the currently known regulatory mechanisms of NURR1 and provide a brief overview of its participation in pathological alterations.

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“…Cells were treated with AG-120 or 5-FU after being cultured with low glucose level media followed by low MgSO4 (0.08 mM). After 8-10 days upon completing the experiments, cells were fixed in a reagent containing 80% methanol and stained with 0.5% (w/v) crystal violet solution for 10 minutes (29). To determine the relative proliferation of the cells, the dye was extracted using 10% glacial acetic acid, and the associate absorbance was measured at 600 nm by a Promega GloMax plate reader.…”

Section: Clonogenic Assaymentioning

confidence: 99%

Targeting wild-type IDH1 enhances chemosensitivity in pancreatic cancer

Zarei

Hajihassani

Hue

et al. 2023

Preprint

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Pancreatic cancer (PC) is one of the most aggressive types of cancer, with a five-year overall survival rate of 12% among all-comers. Current systemic therapeutic options are limited to cytotoxic chemotherapies which have limited clinical efficacy and are often associated with development of drug resistance. Analysis of The Cancer Genome Atlas showed that wild-type isocitrate dehydrogenase (wtIDH1) is overexpressed in pancreatic tumors. In this study, we focus on the potential roles of wtIDH1 in pancreatic cancer chemoresistance. We found that treatment of pancreatic cancer cells with chemotherapy induced expression of wtIDH1, and this serves as a key resistance factor. The enzyme is protective to cancer cells under chemotherapy-induced oxidative stress by producing NADPH and alpha-ketoglutarate to maintain redox balance and mitochondrial function. An FDA-approved mutant IDH1 inhibitor, ivosidenib (AG-120), is actually a potent wtDH1 inhibitor under a nutrient-deprived microenvironment, reflective of the pancreatic cancer microenvironment. Suppression of wtIDH1 impairs redox balance, results in increased ROS levels, and enhances chemotherapy induced apoptosis in pancreatic cancer vis ROS damage in vitro. In vivo experiments further revealed that inhibiting wtIDH1 enhances chemotherapy anti-tumor effects in patient-derived xenografts and murine models of pancreatic cancer. Pharmacologic wtIDH1 inhibition with ivosidenib represents an attractive option for combination therapies with cytotoxic chemotherapy for patients with pancreatic cancer. Based on these data, we have initiated phase Ib trial combining ivosidenib and multi-agent chemotherapy in patients with pancreatic cancer (NCT05209074).

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Nuclear Receptor 4A2 (NR4A2/NURR1) Regulates Autophagy and Chemoresistance in Pancreatic Ductal Adenocarcinoma

Cited by 9 publications

References 43 publications

Wild-type IDH1 inhibition enhances chemotherapy response in melanoma

Wild-type IDH1 inhibition enhances chemotherapy response in melanoma

Mechanisms of NURR1 Regulation: Consequences for Its Biological Activity and Involvement in Pathology

Targeting wild-type IDH1 enhances chemosensitivity in pancreatic cancer

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