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 H.; Shire, Abdirashid M.; Cazanave, Sophie C.; Montoya, Damian P.; Mettler, Teresa A.; Burgart, Lawrence J.; Nagorney, David M.; Thibodeau, Stephen N.; Cunningham, Julie M.; Lai, Jenn‐Haung; Roberts, Lewis R.

doi:10.1016/j.jhep.2008.05.015

Cited by 43 publications

(40 citation statements)

References 71 publications

(84 reference statements)

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“…One of the roles of WWOX protein is participation in steroid hormone metabolism (14,15). Results of previous studies showed that WWOX is also associated with apoptosis, proliferation, adhesion and cell signaling pathways (16)(17)(18)(19). Additionally, WWOX has been shown to bind to PPxY motif-containing proteins, and inactivate their transcription transactivation function by sequestering them in the cytoplasm (20,21).…”

Section: Introductionmentioning

confidence: 99%

The WWOX tumor suppressor gene in endometrial adenocarcinoma

Płuciennik

Kośla

Wójcik‐Krowiranda

et al. 2013

International Journal of Molecular Medicine

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Abstract. Endometrial cancer is a lethal malignancy, the causes of which remain to be determined. The aim of the present study, carried out on tumor samples from 79 patients, was to evaluate the role of the WWOX tumor suppressor gene in endometrial adenocarcinoma. The expression levels of WWOX and its protein content were assessed in normal endometrium and cancer samples. Quantitative PCR was used to assess the correlation between the expression levels of WWOX and the genes involved in the proliferation (MKI67), apoptosis (BAX, BCL2), signal transduction (EGFR), cell cycle (CCNE1, CCND1), cell adhesion (CDH1) and transcription regulation (TP73, NCOR1). The relationship between loss of hetero zygosity (LOH) and WWOX mRNA levels was also investigated using high resolution melting. Results of the present study demonstrated a positive correlation of WWOX expression with BCL2 and CCND1 and a negative correlation with BAX, CDH1, NCOR1 and BCL2/BAX ratio. The results also showed that loss of heterozygosity at two analyzed loci of the WWOX gene is frequent in patients with endometrial cancer and that WWOX expression levels are lower in tumor samples than in normal tissue. In conclusion, WWOX may be involved in endometrial cancer.

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Section: Introductionmentioning

confidence: 99%

The WWOX tumor suppressor gene in endometrial adenocarcinoma

Płuciennik

Kośla

Wójcik‐Krowiranda

et al. 2013

International Journal of Molecular Medicine

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“…Chang et al determined that WWOX is the key factor of p53 in apoptosis (11). WWOX may therefore enhance the apoptosis-inducing activity of p53 (6). In addition, A549 is a p53-positive cell line.…”

Section: Discussionmentioning

confidence: 99%

“…To date, seven alternatively spliced WWOX protein variants have been identified. The aberrant expression of WWOX has been reported in various cancer cell types including breast (2), ovarian (3), prostate (4), gastric (5) and hepatic cancer (6), osteosarcoma (7), and lung cancer (8).…”

Section: Introductionmentioning

confidence: 99%

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WWOX-mediated apoptosis in A549 cells mainly involves the mitochondrial pathway

et al. 2012

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Abstract. The human WWOX gene, known as WW domaincontaining oxidoreductase, is located on 16q23.3-24.1, a chromosome region that spans the common fragile site, FRA16D. Abnormal transcripts or even loss of expression are frequently found in a number of cancer cell types, including breast, ovarian, prostate and lung cancer cells. It has therefore been proposed that the WWOX gene encodes a candidate tumor suppressor, possibly a pro-apoptotic protein. However, the mechanism behind this is not entirely clear. In the present study, we examined the pro-apoptotic action of WWOX using transient expression in A549 cells. We observed that the ectopic expression of WWOX caused apoptosis in A549 cells. We further observed procaspase-3 and procaspase-9 activation and the release of cytochrome C from the mitochondria in A549 cells transfected with pcDNA3.0-WWOX. These data indicate that WWOX induces apoptosis in A549 cells via the mitochondrial pathway.

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“…37,38 It was also shown that forced expression of WWOX could decrease FGF2-mediated proliferation and enhanced JNK inhibitorinduced apoptosis in human hepatocellular carcinoma cells. 39 Recent studies using human lung adenocarcinoma cell lines revealed that ectopic expression of WWOX could cause activation of procaspase-3 and caspase-9, and the release of cytochrome C thus leads to apoptosis. 40 P73, the p53 homolog, was also identified as the binding partner of WWOX through its PPxY motif in the C-terminal domain Tyrosin (Y) 33 in the first domain of WWOX was revealed as the target for phosphorylation by the Src kinase family and Src kinase mediated the phosphorylation of WWOX which enhances its interaction with p73.…”

Section: Wwox Tumor Suppressor's Functionmentioning

confidence: 99%

WWOX, large common fragile site genes, and cancer

Gao

Smith

2015

Exp Biol Med (Maywood)

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WWOX is a gene that spans an extremely large chromosomal region. It is derived from within chromosomal band 16q23.2 which is a region with frequent deletions and other alterations in a variety of different cancers. This chromosomal band also contains the FRA16D common fragile site (CFS). CFSs are chromosomal regions found in all individuals which are highly unstable. WWOX has also been demonstrated to function as a tumor suppressor that is involved in the development of many cancers. Two other highly unstable CFSs, FRA3B (3p14.2) and FRA6E (6q26), also span extremely large genes, FHIT and PARK2, respectively, and these two genes are also found to be important tumor suppressors. There are a number of interesting similarities between these three large CFS genes. In spite of the fact that they are derived from some of the most unstable chromosomal regions in the genome, they are found to be highly evolutionarily conserved and the chromosomal region spanning the mouse homologs of both WWOX and FHIT are also CFSs in mice. Many of the other CFSs also span extremely large genes and many of these are very attractive tumor suppressor candidates. WWOX is therefore a member of a very interesting family of very large CFS genes.

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

Abstract: WWOX induces apoptosis and inhibits human HCC cell growth through a mechanism enhanced by JNK inhibition.

Cited by 43 publications

References 71 publications

The WWOX tumor suppressor gene in endometrial adenocarcinoma

The WWOX tumor suppressor gene in endometrial adenocarcinoma

WWOX-mediated apoptosis in A549 cells mainly involves the mitochondrial pathway

WWOX, large common fragile site genes, and cancer

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