Orphan Nuclear Receptor Nur77 Mediates the Lethal Endoplasmic Reticulum Stress and Therapeutic Efficacy of Cryptomeridiol in Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) commonly possesses chronical elevation of IRE1α-ASK1 signaling. Orphan nuclear receptor Nur77, a promising therapeutic target in various cancer types, is frequently silenced in HCC. In this study, we show that cryptomeridiol (Bkh126), a naturally occurring sesquiterpen...

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Bibliographic Details
Published in:	Cells (Basel, Switzerland) Vol. 11; no. 23; p. 3870
Main Authors:	Li, Xudan, Chen, Quancheng, Liu, Jie, Lai, Shenjin, Zhang, Minda, Zhen, Tidong, Hu, Hongyu, Gao, Xiang, Wong, Alice S T, Zeng, Jin-Zhang
Format:	Journal Article
Language:	English
Published:	Switzerland MDPI AG 01-12-2022 MDPI
Subjects:	Antibodies Apoptosis Biotechnology Carcinoma, Hepatocellular - drug therapy Carcinoma, Hepatocellular - pathology Care and treatment Cell death Chromatography CRISPR Cytotoxicity Diagnosis Drug development drug target Endoplasmic reticulum Endoplasmic Reticulum Stress Endoribonucleases ER stress Health aspects Hepatocellular carcinoma Hepatoma Homeostasis Humans Liver cancer Liver Neoplasms - drug therapy Liver Neoplasms - pathology MAP kinase Medicine, Chinese Membrane potential Mitochondria mitochondrial membrane potential Nur77 protein orphan nuclear receptor Nur77 Orphan Nuclear Receptors - metabolism Protein Serine-Threonine Kinases Proteins Reactive oxygen species Risk factors sesquiterpenoid Therapeutic targets Traditional Chinese medicine China Singapore Grand Island New York United States > US Germany ER stress sesquiterpenoid orphan nuclear receptor Nur77 drug target hepatocellular carcinoma mitochondrial membrane potential
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Summary:	Hepatocellular carcinoma (HCC) commonly possesses chronical elevation of IRE1α-ASK1 signaling. Orphan nuclear receptor Nur77, a promising therapeutic target in various cancer types, is frequently silenced in HCC. In this study, we show that cryptomeridiol (Bkh126), a naturally occurring sesquiterpenoid derivative isolated from traditional Chinese medicine , has therapeutic efficacy in HCC by aggravating the pre-activated UPR and activating the silenced Nur77. Mechanistically, Nur77 is induced to sense IRE1α-ASK1-JNK signaling and translocate to the mitochondria, which leads to the loss of mitochondrial membrane potential (Δψm). The Bkh126-induced aggravation of ER stress and mitochondrial dysfunction result in increased cytotoxic product of reactive oxygen species (ROS). The in vivo anti-HCC activity of Bkh126 is superior to that of sorafenib, currently used to treat advanced HCC. Our study shows that Bkh126 induces Nur77 to connect ER stress to mitochondria-mediated cell killing. The identification of Nur77 as a molecular target of Bhk126 provides a basis for improving the leads for the further development of anti-HCC drugs.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 These authors contributed equally to this work.
ISSN:	2073-4409 2073-4409
DOI:	10.3390/cells11233870