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 R. Roberts

doi:10.1016/j.jhep.2008.05.015

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 R. Roberts

Research output: Contribution to journal › Article

34 Scopus citations

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 language	English (US)
Pages (from-to)	373-383
Number of pages	11
Journal	Journal of hepatology
Volume	49
Issue number	3
DOIs	https://doi.org/10.1016/j.jhep.2008.05.015
State	Published - Sep 2008

Keywords

Apoptosis
Hepatocellular carcinoma
JNK
WWOX

ASJC Scopus subject areas

Hepatology

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10.1016/j.jhep.2008.05.015

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Aderca, I., Moser, C. D., Veerasamy, M., Bani-Hani, A. H., Bonilla-Guerrero, R., Ahmed, K., Shire, A., Cazanave, S. C., Montoya, D. P., Mettler, T. A., Burgart, L. J., Nagorney, D. M., Thibodeau, S. N., Cunningham, J. M., Lai, J. P., & 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 R.

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

Research output: Contribution to journal › Article

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, 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. / 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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title = "The JNK inhibitor SP600129 enhances apoptosis of HCC cells induced by the tumor suppressor WWOX",

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.",

keywords = "Apoptosis, Hepatocellular carcinoma, JNK, WWOX",

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

year = "2008",

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doi = "10.1016/j.jhep.2008.05.015",

language = "English (US)",

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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.

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

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