c-Fos as a Proapoptotic Agent in TRAIL-Induced Apoptosis in Prostate Cancer Cells

Zhang, Xiaoping; Zhang, Liang; Yang, Hongmei; Huang, Xu; Otu, Hasan H.; Libermann, Towia A.; DeWolf, William C.; Khosravi‐Far, Roya; Olumi, Aria F.

doi:10.1158/0008-5472.can-07-1310

Cited by 81 publications

(88 citation statements)

References 42 publications

(54 reference statements)

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“…Although FLIP is known to be regulated at the translational and post-translational levels 14,31 we herein show that hnRNP K can directly bind to the poly(C) element of the FLIP promoter, transcriptionally activating FLIP and consequently preventing apoptosis. Although transcription of the FLIP gene is also regulated by NF-kB, 32 c-Myc, 33 nuclear factor of activated T cells, 34 androgen receptor response element 35 and c-Fos, 36 we found that hnRNP K is indispensable for the transcriptional activation of FLIP. Previous studies have shown that hnRNP K can regulate the expression of TP 9 and gastrin 2 post-transcriptionally.…”

Section: Discussionmentioning

confidence: 61%

The antiapoptotic protein, FLIP, is regulated by heterogeneous nuclear ribonucleoprotein K and correlates with poor overall survival of nasopharyngeal carcinoma patients

Ic²,

Hsueh

et al. 2010

Cell Death Differ

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Heterogeneous nuclear ribonucleoprotein K (hnRNP K) mediates antiapoptotic activity in part by inducing downstream antiapoptotic genes. To systematically identify hnRNP K targets in nasopharyngeal carcinoma (NPC), affymetrix chips were used to identify genes that were both overexpressed in primary NPC and downregulated by hnRNP K knockdown in NPC-TW02 cells. The resulting gene set included the antiapoptotic gene, FLIP, which was selected for further study. In cells treated with hnRNP K siRNA, TRAIL-induced apoptosis was enhanced and the FLIP protein level was reduced. Promoter, DNA pull-down and chromatin-immunoprecipitation assays revealed that hnRNP K directly interacts with the poly(C) element on the FLIP promoter, resulting in transcriptional activation. Through iTRAQ-mass spectrometric identification of proteins differentially associated with the poly(C) element or its mutant, nucleolin was determined to be a cofactor of hnRNP K for FLIP activation. Furthermore, FLIP was highly expressed in tumor cells, and this high-level expression was significantly correlated with high-level hnRNP K expression (P ¼ 0.002) and poor overall survival (P ¼ 0.015) as examined in 67 NPC tissues. A multivariate analysis confirmed that FLIP was an independent prognostic factor for NPC. Taken together, these findings indicate that FLIP expression is transcriptionally regulated by hnRNP K and nucleolin, and may be a potential prognostic and therapeutic marker for NPC. Heterogeneous nuclear ribonucleoprotein K (hnRNP K) belongs to the hnRNP family of proteins. The members of this family interact directly with DNA and RNA through their K-homology domains and regulate gene expression at multiple levels, including transcription, RNA splicing, RNA stability and translation.1-2 The expression of hnRNP K has been shown to be aberrantly increased in numerous cancers, [3][4][5][6] and we recently reported that high-level hnRNP K expression is correlated with poorer overall survival (OS) and decreased metastasis-free survival among nasopharyngeal carcinoma (NPC) patients.5 Our findings were consistent with those from clinical correlation studies in oral squamous cell carcinoma 4 and prostate cancer. HnRNP K is a nucleocytoplasmic shuttling protein that is primarily located in the nucleus for transcriptional regulation. However, cytoplasmic accumulation of hnRNP K through ERK-mediated phosphorylation of hnRNP K serines-284 and -353 has been reported in cervical carcinoma HeLa, 7 chronic myelogenous leukemia 8 and NPC 9 cells. The tumorigenic activity of hnRNP K appears to be conferred through its ability to increase proliferation, 10 antiapoptotic effects, 9 clonogenic potential 8 and metastasis. 11 These functions may be due, at least in part, to the ability of hnRNP K to upregulate the c-myc, 8,12 thymidine phosphorylase (TP) 9 and eIF4E 10 genes through transcriptional or post-transcriptional regulation. However, the full spectrum of targets regulated by hnRNP K has not as yet been systematically examined.The acquisition of resistance to ...

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Section: Discussionmentioning

confidence: 61%

The antiapoptotic protein, FLIP, is regulated by heterogeneous nuclear ribonucleoprotein K and correlates with poor overall survival of nasopharyngeal carcinoma patients

Ic²,

Hsueh

et al. 2010

Cell Death Differ

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“…However, an elevated cFos expression can also lead to apoptosis in hepatoma cells (Kalra and Kumar, 2004) and hepatocytes (Mikula et al, 2003). Furthermore, recent studies have shown that cFos transcriptionally represses the key antiapoptotic gene c-FLIP(L), greatly sensitising prostate cancer cells to TRAIL-induced apoptosis (Li et al, 2007;Zhang et al, 2007). Hence strategies to increase cFos transcription could be valuable in making malignant cells vulnerable to apoptosis, and HXR9 may synergise with TRAIL and other drugs that induce apoptosis to facilitate enhanced cell killing across a broad range of tumour types.…”

Section: Discussionmentioning

confidence: 99%

HOX transcription factors are potential therapeutic targets in non-small-cell lung cancer (targeting HOX genes in lung cancer)

et al. 2009

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The HOX genes are a family of homeodomain-containing transcription factors that determine the identity of cells and tissues during embryonic development. They are also known to behave as oncogenes in some haematological malignancies. In this study, we show that the expression of many of the HOX genes is highly elevated in primary non-small-cell lung cancers (NSCLCs) and in the derived cell lines A549 and H23. Furthermore, blocking the activity of HOX proteins by interfering with their binding to the PBX co-factor causes these cells to undergo apoptosis in vitro and reduces the growth of A549 tumours in vivo. These findings suggest that the interaction between HOX and PBX proteins is a potential therapeutic target in NSCLC. The HOX genes are a family of homeodomain-containing transcription factors that determine the identity of cells and tissues in early development (Iimura and Pourquié, 2007), and also have key regulatory roles in adult haematopoietic stem cells and their descendants (Abramovich and Humphries, 2005). In addition, HOX genes are often overexpressed in malignant cells and are known to act as oncogenes in some haematopoietic malignancies (Eklund, 2007).Repeated duplication events have given rise to 39 HOX genes in mammals, divided into four groups (A -D) in tightly linked clusters on different chromosomes (Hoegg and Meyer, 2005). The HOX genes are also divided into paralogue groups -genes that have the equivalent position in each cluster (1 -13) -thus HOXA1, for example, is the 3 0 most gene in cluster A (Scott, 1993). Whereas some HOX genes have distinct functions in specific contexts, many others have overlapping or redundant functions, both during early development (McIntyre et al, 2007) and in malignant cells (Eklund, 2007). This redundancy in HOX function is based in part upon the binding of similar DNA sequences and also on the interaction of HOX proteins with a common set of co-factors including PBX and MEIS. PBX and MEIS modify the DNA-binding specificity of HOX proteins, influence the regulation of transcription and are required for many aspects of HOX function (Moens and Selleri, 2006).In addition to haematological malignancies, the HOX genes are also expressed at high levels in many other solid malignancies, although with the exception of melanoma (Morgan et al, 2007), they are not known to have an oncogenic function. A number of studies, focusing on small groups of HOX genes, have shown that some are upregulated in lung cancer (Abe et al, 2006), but the functional significance of this is unknown. Here we present a comprehensive analysis of HOX expression in non-small-cell lung cancer (NSCLC) that reveals that many of the HOX genes have strongly elevated expression in malignant cells. Further, we show that antagonising HOX/PBX binding in the NSCLC cell lines A549 (Lieber et al, 1976) and H23 (Little et al, 1983) induces apoptosis in vitro and causes significant tumour shrinkage in A549 nude mouse models.

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“…Supporting this idea, overexpression of both c-FLIP L and c-FLIP S reduced the cell death induced by the combined treatment of Wit A and TRAIL. It is generally recognized that c-FLIP protein levels can be transcriptionally regulated through the nuclear factor-κB or c-fos pathway [9,39,40] or by ubiquitin-and caspase-mediated degradation [37,[41][42][43]. Recent reports showed that Wit A has a strong ability not only to block completely the binding of the transcription factor to DNA but also to induce the cleavage of NF-κB [4,10].…”

Section: Discussionmentioning

confidence: 99%

Withaferin A sensitizes TRAIL-induced apoptosis through reactive oxygen species-mediated up-regulation of death receptor 5 and down-regulation of c-FLIP

Lee

Min

et al. 2009

Free Radical Biology and Medicine

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c-Fos as a Proapoptotic Agent in TRAIL-Induced Apoptosis in Prostate Cancer Cells

Abstract: Tumor necrosis factor-related apoptosis-inducing ligand

Cited by 81 publications

References 42 publications

The antiapoptotic protein, FLIP, is regulated by heterogeneous nuclear ribonucleoprotein K and correlates with poor overall survival of nasopharyngeal carcinoma patients

The antiapoptotic protein, FLIP, is regulated by heterogeneous nuclear ribonucleoprotein K and correlates with poor overall survival of nasopharyngeal carcinoma patients

HOX transcription factors are potential therapeutic targets in non-small-cell lung cancer (targeting HOX genes in lung cancer)

Withaferin A sensitizes TRAIL-induced apoptosis through reactive oxygen species-mediated up-regulation of death receptor 5 and down-regulation of c-FLIP

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