Cyr61 Expression Confers Resistance to Apoptosis in Breast Cancer MCF-7 Cells by a Mechanism of NF-κB-dependent XIAP Up-Regulation

Lin, Ming Tsan; Chang, Cheng; Chen, Szu-Ta; Chang, Huei Ling; Su, Jen Liang; Chau, Yat‐Pang; Kuo, Min-Liang

doi:10.1074/jbc.m402305200

Cited by 178 publications

(166 citation statements)

References 82 publications

(66 reference statements)

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“…The fact that, in certain circumstances, NF-kB can regulate the expression of the IAPs in a differential manner has recently been demonstrated by others. It has been shown in this regard that connective tissue growth factor Cyr61 triggers activation of NF-kB and subsequent NF-kB-induced upregulation of XIAP but not of cIAP2 in breast carcinoma cells (Lin et al, 2004). Of note, detachment-dependent upregulation of XIAP occurred in each cell line tested in this study.…”

Section: Discussionsupporting

confidence: 47%

Detachment-induced upregulation of XIAP and cIAP2 delays anoikis of intestinal epithelial cells

Liu

et al. 2006

Oncogene

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Detachment of normal epithelial cells from the extracellular matrix triggers apoptosis, a phenomenon called anoikis. Conversely, carcinoma cells tend to be relatively more anoikis-resistant than their normal counterparts, and this increased resistance represents a critical feature of the malignant phenotype. Mechanisms that control susceptibility and resistance to anoikis are not fully understood. It is now known that detachment of non-malignant epithelial cells triggers both pro-and antiapoptotic signals, and it is the balance between these signals and the duration of detachment that determine further fate of the cells. Detachment-induced antiapoptotic events delay anoikis and if cells reattach relatively soon after detachment they survive. Direct regulators of apoptosis responsible for this delay of anoikis are unknown. We found that detachment of non-malignant intestinal epithelial cells triggers upregulation of inhibitors of apoptosis protein (IAP) family, such as X-chromosome-linked inhibitor of apoptosis protein and cellular inhibitor of apoptosis-2 (cIAP2). We demonstrated that this upregulation requires detachmentdependent activation of the transcription factor nuclear factor-jB. We further observed that various IAP antagonists accelerate anoikis, indicating that upregulation of the IAPs delays detachment-triggered apoptosis. We conclude that the IAPs are important regulators of the balance between detachment-triggered life and death signals. Perhaps, not by coincidence, these proteins are often upregulated in carcinomas, tumors composed of cells that tend to be anoikis-resistant.

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Section: Discussionsupporting

confidence: 47%

Detachment-induced upregulation of XIAP and cIAP2 delays anoikis of intestinal epithelial cells

Liu

et al. 2006

Oncogene

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“…Microtubule cytoskeleton dysfunction has been shown to activate NF-kB (Rosette and Karin, 1995; Das and Mechanisms of IL-6 upregulation by paclitaxel T-H Wang et al White, 1997). Most recent reports have suggested activation of NF-kB to be an antiapoptotic mechanism of cancer cells (Dong et al, 2002;Uzzo et al, 2002;Dey et al, 2003;Flynn et al, 2003;Lin et al, 2004), although contrary observations have also been reported (Huang and Fan, 2002). Notably, NF-kB is also an important downstream transcription factor in the TLR4-MyD88 signaling cascade (Takeda et al, 2003) ( Figure 7).…”

Section: Discussionmentioning

confidence: 99%

Paclitaxel (Taxol) upregulates expression of functional interleukin-6 in human ovarian cancer cells through multiple signaling pathways

Chan

Chen

et al. 2006

Oncogene

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Paclitaxel (Taxol) is an antineoplastic agent that specifically targets microtubules and arrests cells at the G2/M phase of the cell cycle. In addition to mitotic arrest, the activation of c-Jun N-terminal kinase (JNK) signaling pathway has been demonstrated to be involved in the process leading to apoptosis. In an attempt to explore what genes are transcriptionally regulated by the activated JNK signaling pathway upon paclitaxel treatment, we used cDNA microarrays to analyse the changes of gene expression in human ovarian cancer cells that were treated with paclitaxel and/or the JNK inhibitor SP600125. Among 20 genes that were specifically regulated by the paclitaxel-activated JNK pathway, interleukin (IL)-6 was shown to elicit function through the JAK-STAT signaling pathway in an autocrine and/or paracrine fashion. Subsequently, we identified that 87.5% of eight tested ovarian cancer lines secreted detectable levels of IL-6, which could be further upregulated 2-3.2 fold by 1 lM paclitaxel. Dissection on regulatory pathways for IL-6 indicated that (i) when ovarian cancer cells were treated with paclitaxel at low but clinically achievable concentrations (exemplified by 1 lM in this study), the JNK signaling pathway was the major stimulator of IL-6 gene regulation and (ii) at suprapharmacologically high concentrations (exemplified by 50 lM), paclitaxel exerted lipopolysaccharide-like effects, most likely through the Toll-like receptor 4 signaling pathway. Collectively, these results suggest that paclitaxel upregulates functional IL-6 expression in human ovarian cancer cells through multiple signaling pathways.

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“…The current results regarding the role of CYR61 in gemcitabine resistance provide a rationale for inhibiting CYR61 or both CTGF and CYR61 in combination with gemcitabine (and nab-paclitaxel) in PDAC patients. Although our study is the first to identify a role for CYR61 in nucleoside transporter expression and gemcitabine resistance, CYR61 has recently been implicated in therapy resistance in the contexts of several other cancers, including renal cell carcinoma (39), breast cancer (58,59), acute myeloid leukemia (60) and ovarian cancer (61), which indicates that CYR61 may be a promising target to improve efficacy of chemotherapy.…”

Section: Discussionmentioning

confidence: 99%

TGF-β-induced stromal CYR61 promotes resistance to gemcitabine in pancreatic ductal adenocarcinoma through downregulation of the nucleoside transporters hENT1 and hCNT3

Hesler¹,

Huang²,

Starr³

et al. 2016

CARCIN

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Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer in part due to inherent resistance to chemotherapy, including the first-line drug gemcitabine. Although low expression of the nucleoside transporters hENT1 and hCNT3 that mediate cellular uptake of gemcitabine has been linked to gemcitabine resistance, the mechanisms regulating their expression in the PDAC tumor microenvironment are largely unknown. Here, we report that the matricellular protein cysteine-rich angiogenic inducer 61 (CYR61) negatively regulates the nucleoside transporters hENT1 and hCNT3. CRISPR/Cas9-mediated knockout of CYR61 increased expression of hENT1 and hCNT3, increased cellular uptake of gemcitabine and sensitized PDAC cells to gemcitabine-induced apoptosis. In PDAC patient samples, expression of hENT1 and hCNT3 negatively correlates with expression of CYR61. We demonstrate that stromal pancreatic stellate cells (PSCs) are a source of CYR61 within the PDAC tumor microenvironment. Transforming growth factor-β (TGF-β) induces the expression of CYR61 in PSCs through canonical TGF-β-ALK5-Smad2/3 signaling. Activation of TGF-β signaling or expression of CYR61 in PSCs promotes resistance to gemcitabine in PDAC cells in an in vitro co-culture assay. Our results identify CYR61 as a TGF-β-induced stromal-derived factor that regulates gemcitabine sensitivity in PDAC and suggest that targeting CYR61 may improve chemotherapy response in PDAC patients.

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Cyr61 Expression Confers Resistance to Apoptosis in Breast Cancer MCF-7 Cells by a Mechanism of NF-κB-dependent XIAP Up-Regulation

Cited by 178 publications

References 82 publications

Detachment-induced upregulation of XIAP and cIAP2 delays anoikis of intestinal epithelial cells

Detachment-induced upregulation of XIAP and cIAP2 delays anoikis of intestinal epithelial cells

Paclitaxel (Taxol) upregulates expression of functional interleukin-6 in human ovarian cancer cells through multiple signaling pathways

TGF-β-induced stromal CYR61 promotes resistance to gemcitabine in pancreatic ductal adenocarcinoma through downregulation of the nucleoside transporters hENT1 and hCNT3

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