The JNK inhibitor SP600129 enhances apoptosis of HCC cells induced by the tumor suppressor WWOX.
OBJECTIVE
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.
Aderca
Ileana
I
Miles and Shirley Fiterman Center for Digestive Diseases and Mayo Clinic Cancer Center, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.
Moser
Catherine D
CD
Veerasamy
Manivannan
M
Bani-Hani
Ahmad H
AH
Bonilla-Guerrero
Ruben
R
Ahmed
Kadra
K
Shire
Abdirashid
A
Cazanave
Sophie C
SC
Montoya
Damian P
DP
Mettler
Teresa A
TA
Burgart
Lawrence J
LJ
Nagorney
David M
DM
Thibodeau
Stephen N
SN
Cunningham
Julie M
JM
Lai
Jin-Ping
JP
Roberts
Lewis R
LR
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis / Q000187:drug effects*; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002885:Chromosomes, Human, Pair 16 / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology*; D019656:Loss of Heterozygosity / Q000235:genetics; D008297:Male; D008875:Middle Aged; D048055:Mitogen-Activated Protein Kinase 8 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010088:Oxidoreductases / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D019311:Staurosporine / Q000494:pharmacology; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D000074584:WW Domain-Containing Oxidoreductase
D004791:Enzyme Inhibitors; D012333:RNA, Messenger; D025521:Tumor Suppressor Proteins; D010088:Oxidoreductases; D000074584:WW Domain-Containing Oxidoreductase; C486071:WWOX protein, human; D048055:Mitogen-Activated Protein Kinase 8; D019311:Staurosporine