The JNK inhibitor SP600129 enhances apoptosis of HCC cells induced by the tumor suppressor WWOX

Background/Aims The FRA16D fragile site gene WWOX is a tumor suppressor that participates in p53-mediated apoptosis. The c-jun N-terminal kinase JNK1 interacts with WWOX and inhibits apoptosis. We investigated the function of WWOX in human hepatocellular carcinoma (HCC) and the effect of JNK inhibit...

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Published in:Journal of hepatology 2008-09, Vol.49 (3), p.373-383
Main Authors: Aderca, Ileana, Moser, Catherine D, Veerasamy, Manivannan, Bani-Hani, Ahmad H, Bonilla-Guerrero, Ruben, Ahmed, Kadra, Shire, Abdirashid, Cazanave, Sophie C, Montoya, Damian P, Mettler, Teresa A, Burgart, Lawrence J, Nagorney, David M, Thibodeau, Stephen N, Cunningham, Julie M, Lai, Jin-Ping, Roberts, Lewis R
Format: Article
Language:English
Subjects:
Adult
Aged
Aged, 80 and over
Apoptosis
Apoptosis - drug effects
Biological and medical sciences
Carcinoma, Hepatocellular - metabolism
Carcinoma, Hepatocellular - pathology
Cell Line, Tumor
Cell Proliferation - drug effects
Chromosomes, Human, Pair 16 - genetics
Enzyme Inhibitors - pharmacology
Female
Gastroenterology and Hepatology
Gastroenterology. Liver. Pancreas. Abdomen
Gene Expression Regulation
Hepatocellular carcinoma
Humans
JNK
Liver Neoplasms - metabolism
Liver Neoplasms - pathology
Liver. Biliary tract. Portal circulation. Exocrine pancreas
Loss of Heterozygosity - genetics
Male
Medical sciences
Middle Aged
Mitogen-Activated Protein Kinase 8 - antagonists & inhibitors
Mitogen-Activated Protein Kinase 8 - metabolism
Oxidoreductases - genetics
Oxidoreductases - metabolism
RNA, Messenger - metabolism
Staurosporine - pharmacology
Tumor Suppressor Proteins - genetics
Tumor Suppressor Proteins - metabolism
Tumors
WW Domain-Containing Oxidoreductase
WWOX
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Summary:Background/Aims The FRA16D fragile site gene WWOX is a tumor suppressor that participates in p53-mediated apoptosis. The c-jun N-terminal kinase JNK1 interacts with WWOX and inhibits apoptosis. We investigated the function of WWOX in human hepatocellular carcinoma (HCC) and the effect of JNK inhibition on WWOX-mediated apoptosis. Methods Allelic imbalance on chromosome 16 was analyzed in 73 HCCs using 53 microsatellite markers. WWOX mRNA in HCC cell lines and primary HCCs was measured by real-time RT-PCR. Effects of WWOX on proliferation and apoptosis and the interaction between WWOX and JNK inhibition were examined. Results Loss on chromosome 16 occurred in 34 of 73 HCCs. Of 11 HCC cell lines, 2 had low, 7 intermediate, and 2 had high WWOX mRNA. Of 51 primary tumors, 23 had low WWOX mRNA. Forced expression of WWOX in SNU387 cells decreased FGF2-mediated proliferation and enhanced apoptosis induced by staurosporine and the JNK inhibitor SP600129. Conversely, knockdown of WWOX in SNU449 cells using shRNA targeting WWOX increased proliferation and resistance to SP600129-induced apoptosis. Conclusions WWOX induces apoptosis and inhibits human HCC cell growth through a mechanism enhanced by JNK inhibition.
ISSN:0168-8278
1600-0641
DOI:10.1016/j.jhep.2008.05.015