Induction of endoplasmic reticulum stress and apoptosis by a marine prostanoid in human hepatocellular carcinoma.

Abstract

BACKGROUND/AIMS:

Hepatocellular carcinoma is a very common malignancy and is highly chemoresistant to currently available chemotherapeutic agents. We isolated a marine prostanoid, bromovulone III, from soft coral Clavularia viridis and found that it displayed effective anti-tumor activity in human hepatocellular carcinoma. The anti-tumor mechanism has been delineated in this study.

METHODS:

Anti-tumor efficacy and apoptotic cell death were examined by sulforhodamine B and Hoechst 33342 assays. Rhodamine 123 was used to measure the change of mitochondrial membrane potential. Immunoprecipitation and Western blotting detect the involvement of several apoptosis-related proteins. Electron microscopic examination detects the morphological change of mitochondria and endoplasmic reticulum (ER).

RESULTS:

Bromovulone III primarily induced mitochondria-related activation of caspase-9 and -3 in several tumor types, such as prostate cancer PC-3 and acute promyelocytic leukemia HL-60 cells. However, it primarily induced the activation of m-calpain, caspase-12, and transcription factor CHOP/GADD153 in hepatocellular carcinoma Hep3B cells, suggesting the involvement of ER stress. Furthermore, a secondary mitochondrial swelling and depolarization of mitochondrial membrane potential were subsequently triggered after ER stress, suggesting the crosstalk between ER and mitochondria.

CONCLUSIONS:

It is suggested that bromovulone III induces apoptosis in Hep3B cells through a mechanism that induces ER stress and leads to activation of CHOP/GADD153 and caspase-12.

• Authors: Po-Cheng Chiang, Chung-Liang Chien, Shiow-Lin Pan, Wen-Pin Chen, Che-Ming Teng, Ya-Ching Shen, Jih-Hwa Guh
• Journal: Journal of hepatology (J Hepatol) Vol. 43 Issue 4 Pg. 679-86 (Oct 2005) ISSN: 0168-8278 [Print] Netherlands
• PMID: 16023761 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Prostaglandins

Topics

• Apoptosis (drug effects)
• Carcinoma, Hepatocellular
• Cell Line, Tumor
• Endoplasmic Reticulum (drug effects, pathology, physiology, ultrastructure)
• Humans
• Liver Neoplasms
• Oxidative Stress (physiology)
• Prostaglandins (pharmacology)