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

Ileana Aderca, Catherine D. Moser, Manivannan Veerasamy, Ahmad H. Bani-Hani, Ruben Bonilla-Guerrero, Kadra Ahmed, Abdirashid Shire, Sophie C. Cazanave, Damian P. Montoya, Teresa A. Mettler, Lawrence J. Burgart, David M. Nagorney, Stephen N Thibodeau, Julie M Cunningham, Jin Ping Lai, Lewis Rowland Roberts

Research output: Contribution to journalArticle

33 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)373-383
Number of pages11
JournalJournal of Hepatology
Volume49
Issue number3
DOIs
StatePublished - Sep 2008

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Hepatocellular Carcinoma
Apoptosis
Neoplasms
Chromosomes, Human, Pair 16
Messenger RNA
Allelic Imbalance
Cell Line
Staurosporine
JNK Mitogen-Activated Protein Kinases
Fibroblast Growth Factor 2
Microsatellite Repeats
Small Interfering RNA
Real-Time Polymerase Chain Reaction
Growth
Genes

Keywords

  • Apoptosis
  • Hepatocellular carcinoma
  • JNK
  • WWOX

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Aderca, I., Moser, C. D., Veerasamy, M., Bani-Hani, A. H., Bonilla-Guerrero, R., Ahmed, K., ... Roberts, L. R. (2008). The JNK inhibitor SP600129 enhances apoptosis of HCC cells induced by the tumor suppressor WWOX. Journal of Hepatology, 49(3), 373-383. https://doi.org/10.1016/j.jhep.2008.05.015

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

In: Journal of Hepatology, Vol. 49, No. 3, 09.2008, p. 373-383.

Research output: Contribution to journalArticle

Aderca, I, Moser, CD, Veerasamy, M, Bani-Hani, AH, Bonilla-Guerrero, R, Ahmed, K, Shire, A, Cazanave, SC, Montoya, DP, Mettler, TA, Burgart, LJ, Nagorney, DM, Thibodeau, SN, Cunningham, JM, Lai, JP & Roberts, LR 2008, 'The JNK inhibitor SP600129 enhances apoptosis of HCC cells induced by the tumor suppressor WWOX', Journal of Hepatology, vol. 49, no. 3, pp. 373-383. https://doi.org/10.1016/j.jhep.2008.05.015
Aderca I, Moser CD, Veerasamy M, Bani-Hani AH, Bonilla-Guerrero R, Ahmed K et al. The JNK inhibitor SP600129 enhances apoptosis of HCC cells induced by the tumor suppressor WWOX. Journal of Hepatology. 2008 Sep;49(3):373-383. https://doi.org/10.1016/j.jhep.2008.05.015
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 Rowland. / The JNK inhibitor SP600129 enhances apoptosis of HCC cells induced by the tumor suppressor WWOX. In: Journal of Hepatology. 2008 ; Vol. 49, No. 3. pp. 373-383.
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abstract = "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.",
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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 Rowland

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