Targeting A20 enhances TRAIL-induced apoptosis in hepatocellular carcinoma cells

ArticleinBiochemical and Biophysical Research Communications 418(2):433-8 · February 2012with10 Reads
DOI: 10.1016/j.bbrc.2012.01.056 · Source: PubMed
A20 was initially identified as a primary gene product following TNF α treatment in human umbilical vein endothelial cells. Increased A20 expression is associated with tumorigenesis in many cancers, whereas the loss of A20 function is linked to lymphoma. It has been reported that A20 protects cells from TRAIL-induced apoptosis; however, the mechanism by which A20 is involved is still largely unknown. Our results indicate that TRAIL induces the hepatocellular carcinoma apoptosis associated with A20 knockdown in a concentration-dependent manner. TRAIL-induced apoptosis requires p18 caspase-8 activation, and, the activation of caspase-8 is at least in part, due to the direct cleavage of RIP1 by A20 knockdown. These findings suggest that A20 modulates the sensitivity to TRAIL by RIP1 ubiquitination, thereby repressing the recruitment and activation of pro-caspase-8 into the active form caspase-8. Thus, our study suggests that A20 protects against TRAIL-induced apoptosis through the regulation of RIP1 ubiquitination.
    • "Previous studies show that A20 expression is absent in normal liver, but is present in hepatitis tissue [28, 29]. A20 is also expressed in HCC tissues probably due to the inflammatory environment of HCC [30]. The data deposited in the GEO profile database shows that the A20 mRNA level in HCC with metastasis is decreased compared to that in HCC without metastasis (http://www. "
    [Show abstract] [Hide abstract] ABSTRACT: Metastasis of hepatocellular carcinoma (HCC) can be facilitated by TNF-α, a prototypical inflammatory cytokine in the HCC microenvironment. A20 is a negative regulator of NF-κB signaling pathway. In the present study we ask whether A20 plays a role in HCC metastasis. We found that A20 expression was downregulated in the invasive cells of microvascular invasions (MVI) compared with the noninvasive cells in 89 tissue samples from patients with HCC by immunochemistry methods. Overexpression of A20 in HCC cell lines inhibited their motility induced by TNF-α. Furthermore, the overexpression of A20 inhibited epithelial-mesenchymal transition (EMT), FAK activation and RAC1 activity. By contrast, knockdown of A20 in one HCC cell line results in the converse. In addition, the overexpression of A20 restrained the formation of MVI in HCC xenograft in nude mice treated with TNF-α. All the results suggested that A20 functioned as a negative regulator in motility of HCC cells induced by TNF-α.
    Full-text · Article · Feb 2016
    • "c Cells were serum starved overnight followed by treated with TNFα (10 ng/mL) for the indicated times and then cell lysates were harvested and subjected to Western blot assay and probed with the indicated antibodies. d Cells were transfected with IκBα or empty vector plasmid for 24 h and then cell lysates were harvested and subjected to Western blot assay and probed with the indicated antibodies finding of Dong BF et al. [18], in that they also reported that A20 was highly expressed in human HCC tissues. In addition, analyzing the association of A20 expression with clinicopathologic characteristics in 143 HCC patients by tissue microarray revealed a significant negative correlation between A20 expression and tumor size, thrombus formation, capsular invasion, TNM stage and serum AFP, which are all hallmarks for poor prognosis of HCC [38]. "
    [Show abstract] [Hide abstract] ABSTRACT: Aberrant expression of A20 has been reported in several human malignancies including hepatocellular carcinoma (HCC). However, its clinical relevance and potential role in HCC remain unknown. Quantitative PCR, Western blots and immunohistochemistry analyses were used to quantify A20 expression in HCC samples and cell lines. The correlation of A20 expression with clinicopathologic features was analyzed in a cohort containing 143 patients with primary HCC. Kaplan-Meier curves were used to evaluate the association between A20 expression and patient survival. Functional studies were performed to determine the effects of A20 on proliferation and metastasis of HCC cells in vitro and in vivo. Expression of A20 was increased in HCC tissues and cell lines. Increased expression of A20 was negatively correlated with the tumor size, TNM stage, tumor thrombus formation, capsular invasion and serum AFP levels. Patients with higher A20 expression had a prolonged disease-free survival and overall survival than those with lower A20 expression. Forced expression of A20 significantly inhibited the proliferative and invasive properties of HCC cells both in vitro and in vivo, whereas knockdown of A20 expression showed the opposite effects. Further studies revealed that expression of A20 was inversely correlated with Twist1 levels and NF-κB activity in HCC tissues and cell lines. A20-induced suppression of proliferation and migration of HCC cells were mainly mediated through inhibition of Twist1 expression that was regulated at least partly by A20-induced attenuation of NF-κB activity. Our results demonstrate that A20 plays a negative role in the development and progression of HCC probably through inhibiting Twist1 expression. A20 may serve as a novel prognostic biomarker and potential therapeutic target for HCC patients.
    Full-text · Article · Nov 2015
    • "In human glioblastoma, A20 inhibits TRAIL-induced apoptosis by preventing K63-linked polyubiquitinated RIP1 binding to the caspase-8 protease p18 domain, which then blocks caspase-8 dimerization and cleavage [142] . In hepatocellular carcinoma cells, A20 pro-tects against TRAIL-induced apoptosis through the regulation of RIP1 ubiquitination [143]. Moreover, A20 also can inhibit the proteolytic cleavage of apical caspases-8 and 2, executioner caspases-3 and 6, Bid cleavage, and the release of cytochrome c, thus preserving mitochondrion integrity. "
    [Show abstract] [Hide abstract] ABSTRACT: Abstract: Ionizing radiation (IR) plays an important role in the treatment of epithelial tumors, such as lung and prostate cancer, by wounding and killing cancer cells. How- ever, IR also activates sophisticated anti-apoptotic transcriptional factors such that can- cer cells fail to repair DNA damage and obtain resistance to apoptosis under conditions of radiotherapy. Among these transcription factors, the transcription factor nuclear factor kappa B (NF-κB) is recognized as a key feature for protecting cells from apopto- sis in most cell types. Moreover, the induction of radioresistance is mediated by several genes that are regulated by NF- κB. The primary purpose of this review is to introduce the studies of the signaling mechanisms of IR in NF-κB activation, such as ROS/NF-κB, ATM or DNA-PK/MAPKK/ p90rsk, PI3K/AKT/IKK and k-ras/c-raf/ MEKK/ NF-κB pathways. Moreover, we describe how the expression of the target genes (e.g., XIAP, A20, FLIP, Bcl-xL) are induced by NF-κB to regulate the activation of survival signaling pathways and to inhibit apoptotic signaling pathways. In addition, IR activates NF-κB to express cell cycle-specific genes, for example cyclin D1, which is associated with reinforcing radioresistance. We exhibit the signaling pathways that are induced by IR stimulation of NF-κB and illustrate the molecular mechanisms of radioresistance.
    Full-text · Article · Apr 2015
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