Adhesion and Rac1-dependent Regulation of Biglycan Gene Expression by Transforming Growth Factor-β

Groth, S.; Schulze, Maren; Kalthoff, Holger; Fändrich, F.; Ungefroren, Hendrik

doi:10.1074/jbc.m504249200

Cited by 44 publications

(52 citation statements)

References 42 publications

(45 reference statements)

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“…Among them, we focused our attention on BGN, a proteoglycan known to be a TGF-β repressor. 35 In cancer, seemingly contradicting data have revealed that increased BGN expression is linked with poor prognosis, 36 whereas its overexpression was associated with inhibition of cancer cell growth. 37,38 We investigated the loss of BGN in the absence of TAp73 (W1 cells) and revealed that Bgn expression was drastically reduced in TAp73-deficient cells compared with that in 4A cells as well as in Panc1 cells transfected with TAp73 siRNA compared with that in Panc1 cells transfected with siCtr (Figure 4d).…”

Section: Resultsmentioning

confidence: 99%

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: Resultsmentioning

confidence: 99%

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

et al. 2016

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“…5B and C). We (30) and others (36) have shown previously that TGF-ß1 activates the p38 MAPK pathway in Panc-1 cells which is involved in K-ras-mediated cell migration in these cells (37). It was therefore of interest to analyse whether specific Src inhibition affected p38 phosphorylation in these cells.…”

Section: Src Inhibition Does Not Interfere With Tgf-ß1-induced Rsmad mentioning

confidence: 99%

“…The conditions for quantitative real-time PCR (qPCR) as well as PCR oligonucleotide primer sequences for ß-actin, TATA-box binding protein (TBP) and GAPDH (30), E-cadherin and Snail2/Slug (31) were described in detail earlier. Real-time PCR was performed on an I-cycler with IQ software (Bio-Rad, München, Germany).…”

Section: Rna Isolation and Quantitative Real-time Rt-pcr Analysismentioning

confidence: 99%

Differential roles of Src in transforming growth factor-ß regulation of growth arrest, epithelial-to-mesenchymal transition and cell migration in pancreatic ductal adenocarcinoma cells

Ungefroren

Sebens²,

Groth³

et al. 2011

Int J Oncol

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Abstract. Both transforming growth factor (TGF)-ß and the non-receptor tyrosine kinase Src play major roles during tumorigenesis by regulating cell growth, epithelial-to-mesenchymal transition (EMT), migration/invasion and metastasis, but little is known about the signaling crosstalk between them. To interfere with Src function in vitro and in vivo many studies have employed the pharmacologic Src inhibitors PP2 and PP1. Both agents have recently been shown to be powerful inhibitors of TGF-ß receptor type I/ALK5 and type II. As this situation prohibited any definite conclusions with respect to the relative contribution of TGF-ß vs. Src signaling, we decided to reappraise a potential role of Src in TGF-ß1-mediated cellular responses using RNA and dominant-negative (dn) interference to block Src expression and function, respectively. In TGF-ß-responsive pancreatic ductal adenocarcinoma (PDAC) cells, we show that Src is activated by TGF-ß1 and that its specific inhibition strongly attenuated basal proliferation and enhanced TGF-ß1-mediated growth arrest. However, Src inhibition was unable to impair TGF-ß1-controlled EMT as evidenced by cell morphology and regulation of the epithelial marker E-cadherin. Despite its dispensibility for TGF-ß-induced EMT, specific inhibition of Src dramatically reduced basal and TGF-ß1-induced cell migration in Panc-1 cells as measured with a novel real-time migration assay (xCELLigence DP system). Biochemically, dnSrc inhibition failed to block TGF-ß1/ALK5-induced activation of Smad2 and Smad3, but partially inhibited transcriptional activation of TGF-ß/Smad-responsive reporter genes, and effectively blocked basal and TGF-ß1-induced activation of p38 MAPK. Together, the data provide evidence for a role of Src in the regulation of basal proliferation as well as in basal and TGF-ß1-mediated cell motility but not EMT in TGF-ß-responsive pancreatic (tumor) cells. IntroductionSrc kinases are non-receptor intracellular tyrosine kinases that mediate a variety of cellular responses. The prototype member p60Src is the product of the proto-oncogene c-Src, and is the cellular homolog of the Rous sarcoma virus transforming protein v-Src. Src kinases are involved in numerous signaling pathways controlling proliferation, migration, adhesion, and angiogenesis (1). Src together with · V ß3 integrin promotes anchorage-independent growth and metastasis (2) and recent data have revealed that transient activation of Src by immortalized mammary epithelial cells triggered an inflammatory response that resulted in the initiation and maintenance of cellular transformation and a switch from a non-transformed to a transformed phenotype (3). Src mediates signaling from many types of receptors including receptor tyrosine kinases (EGF-R), integrins, and G-protein-coupled receptors such as proteinase-activated receptors (PARs) (4). Src is required for EGF-R stimulated DNA synthesis and has been reported to stimulate IGF-I-dependent cell proliferation by increasing IGF-I receptor number (5). Moreover, overexpression...

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“…14,[22][23][24][25][26][27] We found ALK1 to be expressed in both tumor tissue from pancreatic carcinoma patients and in the majority of established pancreatic carcinoma cell lines. In vitro, (ca)ALK1 inhibited basal proliferation, possibly via induction of p21 WAF1 , and thus synergized with TGF-b/ALK5 signaling in the induction of growth arrest.…”

mentioning

confidence: 92%

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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Adhesion and Rac1-dependent Regulation of Biglycan Gene Expression by Transforming Growth Factor-β

Cited by 44 publications

References 42 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

Differential roles of Src in transforming growth factor-ß regulation of growth arrest, epithelial-to-mesenchymal transition and cell migration in pancreatic ductal adenocarcinoma cells

Antitumor activity of ALK1 in pancreatic carcinoma cells

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