Smad4-dependent TGF-β Signaling Suppresses RON Receptor Tyrosine Kinase-dependent Motility and Invasion of Pancreatic Cancer Cells

Zhao, Shujie; Ammanamanchi, Sudhakar; Brattain, Michael G.; Cao, Lin; Thangasamy, Amalraj; Wang, Jing; Freeman, James W.

doi:10.1074/jbc.m800154200

Cited by 44 publications

(61 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Additionally, it has been reported that loss of tumor suppressor SMAD4 expression contributes to aberrant increases in RON expression. 55 We showed frequent SMAD4 copy loss in GEC (28%), which provides a mechanistic explanation for RON overexpression observed in those tumors. Also, RON upregulation as a result of Kras mutation has been suggested in pancreatic cancer; 25 however, no Kras mutations were detected in our samples, suggesting that this mechanism is rare in GEC, consistent with previous reports in reference 63.…”

Section: ©2 0 1 1 L a N D E S B I O S C I E N C E D O N O T D I S Tmentioning

confidence: 97%

“…SMAD4, which is frequently deleted in cancer and associated with increased RON expression, 55 had a GCN by qPCR of 1.35 or less in 26% of samples (14/53; five cell lines and nine tissues); decreased SMAD4 copy number did not occur in the setting of high MST1R GCN ( Table 3). As in the cell lines, we observed that the pattern of copy number alterations in MST1R was frequently parallel to those detected for MET.…”

Section: ©2 0 1 1 L a N D E S B I O S C I E N C E D O N O T D I S Tmentioning

confidence: 99%

See 1 more Smart Citation

RON(MST1R)is a novel prognostic marker and therapeutic target for gastroesophageal adenocarcinoma

Catenacci

Cervantes

Yala

et al. 2011

Cancer Biology & Therapy

107

View full text Add to dashboard Cite

Section: ©2 0 1 1 L a N D E S B I O S C I E N C E D O N O T D I S Tmentioning

confidence: 97%

Section: ©2 0 1 1 L a N D E S B I O S C I E N C E D O N O T D I S Tmentioning

confidence: 99%

RON(MST1R)is a novel prognostic marker and therapeutic target for gastroesophageal adenocarcinoma

Catenacci

Cervantes

Yala

et al. 2011

Cancer Biology & Therapy

107

View full text Add to dashboard Cite

“…Inhibition of RON has implicated its signaling for PDAC cell growth and survival in preclinical studies (2)(3)(4)(5)(6)10). Various studies have shown that therapeutic antibodies and TKIs specific to RON inhibit tumor growth mediated by pancreatic, colon, and breast cancer cells in mouse tumor xenograft models (7,12,13,31).…”

Section: Discussionmentioning

confidence: 99%

Synergistic Activities of MET/RON Inhibitor BMS-777607 and mTOR Inhibitor AZD8055 to Polyploid Cells Derived from Pancreatic Cancer and Cancer Stem Cells

Zeng

Sharma

Zhou

et al. 2014

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

Tyrosine kinase inhibitor BMS-777067 is an inhibitor of RON/MET receptor tyrosine kinases currently under clinical trials. Here, we report the synergistic activity of BMS-777607 in combination with mTOR inhibitor AZD8055 in killing chemoresistant pancreatic cancer and cancer stem cells. Treatment of pancreatic cancer L3.6pl cells with BMS-777607 alone inhibited clonogenic growth and moderately induced apoptotic death. However, BMS-777607 caused extensive polyploidy in L3.6pl cells through inhibition of aurora kinase B activity, independent of RON expression. In contrast, L3.6pl-derived cancer stem cells were highly resistant to BMS-777607-induced growth inhibition and apoptosis. The effect of BMS-777607 on induction of cancer stem cell polyploidy was also weak. BMS-777607-induced polyploidy features a predominant cell population with 8N chromosome content in both L3.6pl and cancer stem cells. These cells also showed decreased sensitivity toward chemotherapeutics by increased survival of IC 50 values in response to doxorubicin, cisplatin, methotrexate, 5-fluorouracial, and gemcitabine. Among a panel of chemical inhibitors that target different signaling proteins, we found that BMS-777607 in combination with mTOR inhibitor AZD8055 exerted synergistic effects on L3.6pl and cancer stem cells. More than 70% of L3.6pl and cancer stem cells lost their viability when both inhibitors were used. Specifically, BMS-777607 in combination with inhibition of mTORC2, but not mTORC1, was responsible for the observed synergism. Our findings demonstrate that BMS-777607 at therapeutic doses exerts inhibitory activities on pancreatic cancer cells but also induces polyploidy insensitive to chemotherapeutics. Combination of BMS-777607 with AZD8055 achieves the maximal cytotoxic effect on pancreatic cancer and cancer stem cells. Mol Cancer Ther; 13(1); 37-48. Ó2013 AACR.

show abstract

“…A recent report by Levy and Hill (16) indicates that TGFh may activate EMT in tumor cells, including pancreatic cancer cell lines that lack Smad4, although others have reported the requirement of Smad signaling in EMT (17)(18)(19). We recently found that restoring Smad4 in pancreatic cancer cells deficient in Smad4 inhibited TGFh-mediated invasion by in vitro assays (20). However, this study (20) did not establish whether Smad4 might influence EMT or whether the inhibition of invasion by Smad4 observed by in vitro assays might translate to inhibition of metastasis in vivo.…”

Section: Introductionmentioning

confidence: 94%

Inhibition of STAT3Tyr705 Phosphorylation by Smad4 Suppresses Transforming Growth Factor β–Mediated Invasion and Metastasis in Pancreatic Cancer Cells

et al. 2008

Self Cite

View full text Add to dashboard Cite

The role of Smad4 in transforming growth factor B (TGFB)-mediated epithelial-mesenchymal transition (EMT), invasion, and metastasis was investigated using isogenically matched pancreatic cancer cell lines that differed only in expression of Smad4. Cells expressing Smad4 showed an enhanced TGFBmediated EMT as determined by increased expression of vimentin and decreased expression of B-catenin and E-cadherin. TGFB-mediated invasion was suppressed in Smad4-intact cells as determined by in vitro assays, and these cells showed a reduced metastasis in an orthotopic model of pancreatic cancer. Interestingly, TGFB inhibited STAT3 Tyr705 phosphorylation in Smad4-intact cells. The decrease in STAT3Tyr705 phosphorylation was linked to a TGFB/Smad4-dependent and enhanced activation of extracellular signalregulated kinases, which caused an increase in serine phosphorylation of STAT3 Ser727 . Down-regulating signal transducer and activator of transcription 3 (STAT3) expression by short hairpin RNA in Smad4-deficient cells prevented TGFBinduced invasion. Conversely, expressing a constitutively activated form of STAT3 (STAT3-C) in Smad4-intact cells enhanced invasion. This study indicates the requirement of STAT3 activity for TGFB-induced invasion in pancreatic cancer cells and implicates Smad4-dependent signaling in regulating STAT3 activity. These findings further suggest that loss of Smad4, leading to aberrant activation of STAT3, contributes to the switch of TGFB from a tumor-suppressive to a tumor-promoting pathway in pancreatic cancer. [Cancer Res 2008;68(11):4221-8]

show abstract

Smad4-dependent TGF-β Signaling Suppresses RON Receptor Tyrosine Kinase-dependent Motility and Invasion of Pancreatic Cancer Cells

Cited by 44 publications

References 41 publications

RON(MST1R)is a novel prognostic marker and therapeutic target for gastroesophageal adenocarcinoma

RON(MST1R)is a novel prognostic marker and therapeutic target for gastroesophageal adenocarcinoma

Synergistic Activities of MET/RON Inhibitor BMS-777607 and mTOR Inhibitor AZD8055 to Polyploid Cells Derived from Pancreatic Cancer and Cancer Stem Cells

Inhibition of STAT3Tyr705 Phosphorylation by Smad4 Suppresses Transforming Growth Factor β–Mediated Invasion and Metastasis in Pancreatic Cancer Cells

Contact Info

Product

Resources

About