Abstract
The acyclic diterpenoid acid geranylgeranoic acid (GGA) has been reported to induce autophagic cell death in several human hepatoma-derived cell lines; however, the molecular mechanism for this remains unknown. In the present study, several diterpenoids were examined for ability to induce XBP1 splicing and/or lipotoxicity for human hepatoma cell lines. Here we show that three groups of diterpenoids emerged: 1) GGA, 2,3-dihydro GGA and 9-cis retinoic acid induce cell death and XBP1 splicing; 2) all-trans retinoic acid induces XBP1 splicing but little cell death; and 3) phytanic acid, phytenic acid and geranylgeraniol induce neither cell death nor XBP1 splicing. GGA-induced ER stress/ unfolded protein response (UPR) and its lipotoxicity were both blocked by co-treatment with oleic acid. The blocking activity of oleic acid for GGA-induced XBP1 splicing was not attenuated by methylation of oleic acid. These findings strongly suggest that GGA at micromolar concentrations induces the so-called lipid-induced ER stress response/UPR, which is oleate-suppressive, and shows its lipotoxicity in human hepatoma cells.
Highlights
Geranylgeranoic acid (GGA) is a natural diterpenoid found in several medicinal herbs including turmeric [1]
We have addressed how GGA initiates signaling linked to GGA-induced cell death in human hepatoma-derived HuH-7 cells
These data strongly demonstrate that polyunsaturated branched-chain fatty acid GGA induces endoplasmic reticulum (ER) stress response/ unfolded protein response (UPR), which may be associated with GGA-induced cell death in human hepatoma cells
Summary
Geranylgeranoic acid (GGA) is a natural diterpenoid found in several medicinal herbs including turmeric [1]. While 4,5-didehydroGGA has been utilized for clinical trials, it has so far not been identified in natural resources. As both 4,5-didehydroGGA and naturally occurring GGA are able to induce cell death in human hepatoma-derived HuH-7 cells [1], we investigated the mechanisms by which natural GGA induces cell death in human hepatoma cells. Over the past 15 years, we have reported various cell-death related effects of GGA at micromolar concentrations in several cell culture systems: loss of mitochondrial membrane potential in HuH-7 cells [3], hyper-production of superoxide in transformed fibroblastic 104C1 cells [7], and rapid downregulation of cyclin D1 in three human hepatoma-derived cell lines
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