TY - JOUR
T1 - The JNK inhibitor SP600129 enhances apoptosis of HCC cells induced by the tumor suppressor WWOX
AU - Aderca, Ileana
AU - Moser, Catherine D.
AU - Veerasamy, Manivannan
AU - Bani-Hani, Ahmad H.
AU - Bonilla-Guerrero, Ruben
AU - Ahmed, Kadra
AU - Shire, Abdirashid
AU - Cazanave, Sophie C.
AU - Montoya, Damian P.
AU - Mettler, Teresa A.
AU - Burgart, Lawrence J.
AU - Nagorney, David M.
AU - Thibodeau, Stephen N.
AU - Cunningham, Julie M.
AU - Lai, Jin Ping
AU - Roberts, Lewis R.
N1 - Funding Information:
This study was supported by National Institutes of Health Grants CA82862 and CA100882, an Industry Research Scholar Award from the Foundation for Digestive Health and Nutrition, a Harold Amos Medical Faculty Development Award from The Robert Wood Johnson Foundation, a generous gift from The Richard M. Schulze Family Foundation, the Miles and Shirley Fiterman Center for Digestive Diseases at the Mayo Clinic, Rochester, MN, the Mayo Clinic Cancer Center and the Mayo Foundation (to L.R.R.).
PY - 2008/9
Y1 - 2008/9
N2 - 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.
AB - 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.
KW - Apoptosis
KW - Hepatocellular carcinoma
KW - JNK
KW - WWOX
UR - http://www.scopus.com/inward/record.url?scp=48449090284&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=48449090284&partnerID=8YFLogxK
U2 - 10.1016/j.jhep.2008.05.015
DO - 10.1016/j.jhep.2008.05.015
M3 - Article
C2 - 18620777
AN - SCOPUS:48449090284
VL - 49
SP - 373
EP - 383
JO - Journal of Hepatology
JF - Journal of Hepatology
SN - 0168-8278
IS - 3
ER -