Journal
CELLS
Volume 11, Issue 23, Pages -Publisher
MDPI
DOI: 10.3390/cells11233870
Keywords
sesquiterpenoid; drug target; orphan nuclear receptor Nur77; ER stress; mitochondrial membrane potential; hepatocellular carcinoma
Categories
Funding
- Natural Science Foundation of China
- Leading Talents in Scientific and Technological Innovation, Double Hundred Talents Program of Fujian Province
- [82073866]
- [81673467]
- [31471273]
- [31461163002/N_HKU740/14]
- [81773601]
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In this study, Bkh126 is shown to have therapeutic efficacy in HCC by activating the silenced Nur77 and aggravating the pre-activated UPR. Mechanistically, Bkh126 induces Nur77 to sense IRE1 alpha-ASK1-JNK signaling and translocate to the mitochondria, leading to cell death.
Hepatocellular carcinoma (HCC) commonly possesses chronical elevation of IRE1 alpha-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 Magnolia officinalis, has therapeutic efficacy in HCC by aggravating the pre-activated UPR and activating the silenced Nur77. Mechanistically, Nur77 is induced to sense IRE1 alpha-ASK1-JNK signaling and translocate to the mitochondria, which leads to the loss of mitochondrial membrane potential (Delta psi m). 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.
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