Smad4/DPC4-dependent Regulation of Biglycan Gene Expression by Transforming Growth Factor-β in Pancreatic Tumor Cells

Chen, Wenbin; Lenschow, Wolfgang; Tiede, Karen; Fischer, Jens W.; Kalthoff, Holger; Ungefroren, Hendrik

doi:10.1074/jbc.m203709200

Cited by 77 publications

(126 citation statements)

References 59 publications

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“…The tumor-suppressor role of TGF-β in pancreatic cancer is mainly mediated by SMAD4, a transcription factor, inactivated in half of invasive PDA 41 and known to induce Bgn expression after TGF-β treatment. 42 Interestingly in TAp73-deficient cells, we observed a decrease in SMAD4 (Figure 6a) consistent with the presence of p53-responsive elements in all promoters of Smad genes. 39 We obtained similar data in vivo with decreased protein levels of SMAD4, SMAD2 and SMAD3 in PDA from CKITA mice compared with CKI mice (Figures 6b and c, and Supplementary Figures S4b and c).…”

Section: Resultssupporting

confidence: 78%

“…Among them, we focused our attention on BGN, a protein close to the TGF-β family that, besides its implication in multiple cancers, is induced by the TGF-β canonical pathway downstream of SMADs signaling 42 and, once the secreted form is cleaved, can favor the release of active TGF-β. 53 Interestingly, this increased amount of free TGF-β is suspected to be associated with increased risk of pancreatic cancer 54 as well as resistance to anticancer treatment 55 and could also be responsible for the promotion of the EMT state.…”

Section: Discussionmentioning

confidence: 99%

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TAp73 loss favors Smad-independent TGF-β signaling that drives EMT in pancreatic ductal adenocarcinoma

et al. 2016

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Advances made in pancreatic cancer therapy have been far from sufficient and have allowed only a slight improvement in global survival of patients with pancreatic ductal adenocarcinoma (PDA). Recent progresses in chemotherapy have offered some hope for an otherwise gloomy outlook, however, only a limited number of patients are eligible because of important cytotoxicity. In this context, enhancing our knowledge on PDA initiation and evolution is crucial to highlight certain weaknesses on which to specifically target therapy. We found that loss of transcriptionally active p73 (TAp73), a p53 family member, impacted PDA development. In two relevant and specific engineered pancreatic cancer mouse models, we observed that TAp73 deficiency reduced survival and enhanced epithelial-to-mesenchymal transition (EMT). Through proteomic analysis of conditioned media from TAp73 wild-type (WT) and deficient pancreatic tumor cells, we identified a secreted protein, biglycan (BGN), which is necessary and sufficient to mediate this pro-EMT effect. Interestingly, BGN is modulated by and modulates the transforming growth factor-β (TGF-β) pathway, a key regulator of the EMT process. We further examined this link and revealed that TAp73 impacts the TGF-β pathway by direct regulation of BGN expression and Sma and Mad-related proteins (SMADs) expression/ activity. Absence of TAp73 leads to activation of TGF-β signaling through a SMAD-independent pathway, favoring oncogenic TGF-β effects and EMT. Altogether, our data highlight the implication of TAp73 in the aggressiveness of pancreatic carcinogenesis through modulation of the TGF-β signaling. By suggesting TAp73 as a predictive marker for response to TGF-β inhibitors, our study could improve the classification of PDA patients with a view to offering combined therapy involving TGF-β inhibitors.

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Section: Resultssupporting

confidence: 78%

Section: Discussionmentioning

confidence: 99%

TAp73 loss favors Smad-independent TGF-β signaling that drives EMT in pancreatic ductal adenocarcinoma

et al. 2016

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“…TbRII function and the ALK5 kinase activity are required for TGF-b/Smad-mediated transcription and growth inhibition PANC-1 cells are known to respond to TGF-b with growth inhibition (Giehl et al, 2000;Chen et al, 2002). To establish whether the antiproliferative response to this growth factor is TbRII-dependent, we employed PANC-1 cells retrovirally transduced in a stable fashion with dominant-negative TbRII (D404G).…”

Section: Resultsmentioning

confidence: 99%

“…Human pancreatic adenocarcinoma PANC-1, and MiaPaCa2 cells were maintained as described earlier (Chen et al, 2002). PANC-1 cells stably transduced with various retroviral vectors were cultured in the presence of 700 mg/ml geneticin (active concentration, Invitrogen, Karlsruhe, Germany).…”

Section: Cell Lines and Cell Culturementioning

confidence: 99%

“…However, equivalent studies at the level of the TGF-b receptors have not been performed in PDAC. We have therefore addressed this issue using a PDAC cell line (PANC-1) that has retained a functional TGF-b/Smad pathway (Chen et al, 2002;Fensterer et al, 2004) and is thus representative of an early stage of pancreatic tumorigenesis. By engineering these cells to express various ALK5 mutants (kinasedefective, Smad activation-incompetent), we present evidence from in vitro and in vivo experiments that both the tumor suppressor function and the prometastatic effects of ALK5 depend on its Smad activating function.…”

Section: Introductionmentioning

confidence: 99%

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Dissecting the role of TGF-beta type I receptor/ALK5 in pancreatic ductal adenocarcinoma: Smad activation is crucial for both the tumor suppressive and prometastatic function

Schniewind¹,

Groth²,

Müerköster³

et al. 2007

Oncogene

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In the present study, we have analysed the effects of transforming growth factor-beta (TGF-b) signaling on the growth behavior of pancreatic carcinoma cells in vitro and on their tumorigenicity in vivo. Ectopic expression of dominant-negative mutants of the TGF-b type II receptor or type I receptor/activin receptor-like kinase 5 (ALK5) in TGF-b-sensitive pancreatic ductal adenocarcinoma PANC-1 cells prevented the TGF-b-induced activation of transfected Smad-responsive reporter genes and growth arrest. The growth-inhibitory effect was mimicked by stable expression of kinase-active ALK5 (ALK5-T204D), and was dependent on ALK5's ability to activate Smad signaling, as a ALK5-derived mutant with an intact kinase domain but deficient in its ability to activate Smads (RImL45) failed to suppress proliferation in the absence of added TGF-b. Moreover, this mutant often displayed opposite effects to those of ALK5-TD and blocked various ligand-induced responses in vitro, indicating that it acts in a dominant-negative fashion to inhibit endogenous wild-type receptors. ALK5-TD-, but not RImL45-TDtransduced cells underwent epithelial-to-mesenchymal transition, exhibited a higher ratio of thrombospondin-1 to vascular endothelial growth factor-A expression and upregulated various metastasis-associated genes. Upon orthotopic transplantation of PANC-1 clones into immunodeficient mice, ALK5-TD, but not RImL45-TD, greatly reduced tumor size and induced the formation of liver metastases in otherwise non-metastatic PANC-1 cells. These results suggest a causal, dominant role for the endogenous Smad2/3 signaling pathway in the tumor suppressor and prometastatic activities of TGF-b in pancreatic tumor cells.

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Antitumor activity of ALK1 in pancreatic carcinoma cells

Ungefroren¹,

Schniewind²,

Groth³

et al. 2007

Intl Journal of Cancer

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In this study, the authors investigated the expression of activin receptor-like kinase 1 (ALK1) in pancreatic carcinoma and evaluated its potential role as a tumor suppressor in vitro and in vivo. Endogenous ALK1 expression was demonstrated by immunohistochemistry in both pancreatic tumor tissue and peritumoral normal tissue from 6 patients and by RT-PCR in 8/12 established pancreatic cancer cell lines. Ectopic expression of a constitutively active (ca) ALK1 mutant in TGF-b sensitive PANC-1 and COLO-357 cells augmented transcriptional activation of a Smad2/3 responsive reporter, and slowed down basal growth in vitro. Both effects were further enhanced by TGF-b/ALK5 stimulation, suggesting largely independent nuclear Smad signaling by both type I receptors. Upon orthotopic transplantation of PANC-1-caALK1 into immunodeficient mice, tumor size was strongly reduced and was associated with a lower microvessel density in the PANC-1-caALK1-derived tumors. In vitro, this mutant efficiently blocked TGF-b-induced epithelial-to-mesenchymal transdifferentiation and suppressed TGF-b/ALK5-mediated activation of the p38 MAPK pathway. Mechanistically, caALK1 silenced MyD118, an immediate TGF-b target gene whose protein product, GADD45b, couples Smad signaling to p38 activation. These results show that ALK1 activation in pancreatic tumor cells is antioncogenic by inducing ALK5-independent growth inhibition and by blocking TGF-b/ALK5-mediated epithelial-to-mesenchymal transdifferentiation and, possibly, invasion and metastatic progression. ' 2007 Wiley-Liss, Inc.

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Smad4/DPC4-dependent Regulation of Biglycan Gene Expression by Transforming Growth Factor-β in Pancreatic Tumor Cells

Cited by 77 publications

References 59 publications

TAp73 loss favors Smad-independent TGF-β signaling that drives EMT in pancreatic ductal adenocarcinoma

TAp73 loss favors Smad-independent TGF-β signaling that drives EMT in pancreatic ductal adenocarcinoma

Dissecting the role of TGF-beta type I receptor/ALK5 in pancreatic ductal adenocarcinoma: Smad activation is crucial for both the tumor suppressive and prometastatic function

Antitumor activity of ALK1 in pancreatic carcinoma cells

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