Induction of endoplasmic reticulum stress and apoptosis by a marine prostanoid in human hepatocellular carcinoma.
OBJECTIVE
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.
Chiang
Po-Cheng
PC
School of Pharmacy, College of Medicine, National Taiwan University, No. 1, Jen-Ai Road, Sect. 1, Taipei, Taiwan, ROC.
Chien
Chung-Liang
CL
Pan
Shiow-Lin
SL
Chen
Wen-Pin
WP
Teng
Che-Ming
CM
Shen
Ya-Ching
YC
Guh
Jih-Hwa
JH
D017209:Apoptosis / Q000187:drug effects*; D006528:Carcinoma, Hepatocellular; D045744:Cell Line, Tumor; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000473:pathology* / Q000502:physiology / Q000648:ultrastructure*; D006801:Humans; D008113:Liver Neoplasms; D018384:Oxidative Stress / Q000502:physiology*; D011453:Prostaglandins / Q000494:pharmacology*
D011453:Prostaglandins