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Induction of nuclear translocation of mutant cytoplasmic p53 by geranylgeranoic acid in a human hepatoma cell line

Significance Statement

Geranylgeranoic acid (GGA) is one of the acyclic diterpenoid derivatives from common intermediates (geranylgeranyl pyrophosphate) in the mevalonate pathway. Several years ago, we identified geranylgeranoic acid  and its derivatives as natural substances in many medicinal herbs including turmeric, schisandra, licorice and Indian gooseberry, suggesting that geranylgeranoic acid  may be a natural substance that prevents and inhibits spontaneous carcinogenesis (J. Lipid Res. 2004; 45: 1092-1103). Recently, we reported a possible cellular mechanism underlying geranylgeranoic acid -induced cell death in human hepatoma cells (HuH-7 cells harboring p53 mutated at Y220C) that is linked to massive accumulation of autophagosomes (we named this an incomplete autophagic response) after Geranylgeranoic acid treatment (Biochem. J. 2011; 440: 63-71).

The novelty of our paper: This is the first report to show that cancer-preventive geranylgeranoic acid , a natural diterpenoid, induced a rapid and valid nuclear translocation of the cytoplasmic p53 in p53-mutated hepatoma cells, giving clues for the molecular mechanism of geranylgeranoic acid -mediated cell death in p53-mutated hepatoma.

The impact of our paper: This paper helps elucidate the molecular mechanism of geranylgeranoic acid -induced cell death through nuclear translocation of mutant p53. 4,5-didehydro derivative of geranylgeranoic acid  has been developed as hepatoma-preventive agents in Japan (N. Engl. J. Med. 1996; 334: 1561-7., ibid 1999; 340: 1046-7., Hepatol. Res. 2011; 41(6): 542-52. BMC. Cancer. 2013; 13: 191.), and American scientists have been interested in our polyprenoic acids for hepatoma prevention in the USA (Gastroenterology. 2004; 127: S294-S302).

Induction of nuclear translocation of mutant cytoplasmic p53 by geranylgeranoic acid in a human hepatoma cell line. - Global Medical Discovery

 

 

 

 

 

 

 

 

 

 

Iwao C, Shidoji Y.

Sci Rep. 2014 Mar 24;4:4419.

Molecular and Cellular Biology, Graduate School of Human Health Science, University of Nagasaki, Academy Hills 1-1-1, Nagayo, Nagasaki 851-2195, Japan.

Abstract

Mutant p53 proteins in human hepatoma cell lines such as HuH-7 (Y220C) and PLC/PRF/5 (R249S) accumulate in the cytoplasm, and lose their transcriptional function. Geranylgeranoic acid (GGA) is a naturally occurring acyclic diterpenoid that induces cell death in both cell lines, but not in HepG2 cells harboring wild-type p53. Here, we demonstrate that micromolar concentrations of geranylgeranoic acid induce a rapid nuclear translocation of cytoplasmic p53 in both p53-mutant cell lines and p53 knockdown attenuates GGA -induced cell death in HuH-7 cells. Cell-free experiments demonstrate that GGA is able to release 670-kD p53-containing complexes from putative huge macromolecular aggregates in post-mitochondrial fractions as revealed on blue-native gradient PAGE. Among several p53-target genes tested, geranylgeranoic acid upregulates PUMA gene expression, and ivermectin, an inhibitor for importin {Alpha}/{Beta}, blocks GGA-induced nuclear translocation of cytoplasmic p53 and suppresses Geranylgeranoic acid-induced upregulation of PUMA mRNA levels in HuH-7 cells. Taken together, these data suggest that GGA Tx stimulates a nuclear translocation of mutant p53 through its dissociation from cytoplasmic aggregates, which may be essential for geranylgeranoic acid -induced cell death.

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