Cell-to-cell adhesion modulates Stat3 activity in normal and breast carcinoma cells

Vultur, Adina; Cao, Jun; Arulanandam, Rozanne; Turkson, James; Jove, Richard; Greer, Peter A.; Craig, Andrew W.B.; Elliott, Bruce E.; Raptis, Leda

doi:10.1038/sj.onc.1207378

Cited by 104 publications

(142 citation statements)

References 55 publications

(84 reference statements)

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“…This situation differs from the KIT kinase-domain mutants in mast cell disease, where STAT is activated strongly and crucial to KIT transforming activity (Ning et al, 2001). In addition, whereas STAT activation is regulated by cell density in a carcinoma model (Vultur et al, 2004), being more strongly activated in subconfluent cultures than in confluent cultures, we did not observe marked increase in STAT activation in subconfluent GIST cultures.…”

Section: Discussioncontrasting

confidence: 83%

“…The density (% confluence) of cancer cell lines, when grown as monolayers in vitro, has been shown to impact phosphorylation of STATs and other signaling proteins (Vultur et al, 2004). In order to determine whether GIST cell density impacts KIT-dependent signaling, we compared phosphoprotein expression, with and without KIT inhibitor treatment, in 100% confluent ('confluent') vs 75% confluent ('subconfluent') GIST48 cells.…”

Section: Density-dependent Effects On Signaling Protein Activationmentioning

confidence: 99%

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KIT oncoprotein interactions in gastrointestinal stromal tumors: therapeutic relevance

Zhu

Fletcher

et al. 2007

Oncogene

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Most gastrointestinal stromal tumors (GISTs) express oncogenic and constitutively active forms of the KIT or platelet-derived growth factor receptor alpha (PDGFRA) receptor tyrosine kinase proteins, and these kinase oncoproteins serve as targets for effective therapies. Given that mutant KIT oncoproteins serve crucial transforming roles in GISTs, we evaluated interactions with the KIT oncoproteins and determined signaling pathways that are dependent on KIT oncogenic activation in GISTs. Tyrosine-phosphorylated KIT oncoproteins interacted with PDGFRA, PDGFRB, phosphatidylinositol 3-kinase (PI3-K) and PKCh in GIST cells, and these interactions were abolished by KIT inhibition with imatinib or PKC412 or KIT RNAi. Notably, tyrosine-phosphorylated PDGFRA was prominent in frozen GIST tumors expressing KIT oncoproteins, suggesting that KIT-mediated PDGFRA phosphorylation is an efficient and biologically consequential mechanism in GISTs. Activated signaling intermediates were identified by immunoaffinity purification of tyrosine-phosphorylated proteins in GIST cells before and after treatment with KIT inhibitors, and these analyses show that GRB2, SHC, CBL and MAPK activation are largely KIT dependent in GISTs, whereas PI3-K, STAT1 and STAT3 activation are partially KIT dependent. In addition, we found that phosphorylation of several tyrosine kinase proteins -including JAK1 and EPHA4 -did not depend on KIT activation. Likewise, paxillin activation was independent of the KIT oncogenic signal. These studies identify signaling pathways that can provide both KIT-dependent and KIT-independent therapeutic synergies in GIST, and thereby highlight clinical strategies that might consolidate GIST therapeutic response to KIT/PDGFRA inhibition.

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Section: Discussioncontrasting

confidence: 83%

Section: Density-dependent Effects On Signaling Protein Activationmentioning

confidence: 99%

KIT oncoprotein interactions in gastrointestinal stromal tumors: therapeutic relevance

Zhu

Fletcher

et al. 2007

Oncogene

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“…Whole-cell extracts were obtained by lysing in 50 mM HEPES, pH 7.4, 150 mM NaCl, 10 mM EDTA, 10 mM Na 4 P 2 O 7 , 100 mM NaF, 2 mM Na 3 VO 4 , protease inhibitor cocktail (Roche) and 1% Triton X-100 as described 46 . Following protein determination by Bradford assay (Bio-Rad Protein Assay Solution, Mississauga, ON), 10-20 mg of clarified cell extract were electrophoresed on 4-12% precast gradient gels (Invitrogen) using the NuPAGE SDS-PAGE Gel system (Invitrogen) with 2-(N-morpholino) ethanesulfonic acid (MES) running buffer and transferred on nitrocellulose membranes (Hybond-C, Bio-Rad).…”

Section: Methodsmentioning

confidence: 99%

Microtubule disruption synergizes with oncolytic virotherapy by inhibiting interferon translation and potentiating bystander killing

et al. 2015

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In this study, we show that several microtubule-destabilizing agents used for decades for treatment of cancer and other diseases also sensitize cancer cells to oncolytic rhabdoviruses and improve therapeutic outcomes in resistant murine cancer models. Drug-induced microtubule destabilization leads to superior viral spread in cancer cells by disrupting type I IFN mRNA translation, leading to decreased IFN protein expression and secretion. Furthermore, microtubule-destabilizing agents specifically promote cancer cell death following stimulation by a subset of infection-induced cytokines, thereby increasing viral bystander effects. This study reveals a previously unappreciated role for microtubule structures in the regulation of the innate cellular antiviral response and demonstrates that unexpected combinations of approved chemotherapeutics and biological agents can lead to improved therapeutic outcomes.

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“…Increasing Cell Density Up-regulates Stat5 DNABinding Activity and Confers Resistance to Dasatinib Recently, Stat3 activity was found to be enhanced with increasing cell-to-cell contact in solid tumor cells (24). To determine whether increasing cell density up-regulates Stat5 activity in K562 CML suspension cultures, Stat5 activity was measured at different cell densities.…”

Section: Dasatinib Induces Apoptosis Of CML Cellsmentioning

confidence: 99%

Dasatinib (BMS-354825) inhibits Stat5 signaling associated with apoptosis in chronic myelogenous leukemia cells

Nam¹,

Williams

Vultur³

et al. 2007

Molecular Cancer Therapeutics

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Dasatinib (BMS-354825) is a novel, oral, potent, multitargeted kinase inhibitor of Bcr-Abl and Src family kinases (SFK) and is a promising cancer therapeutic agent. Preclinical data indicate that dasatinib is 325-fold more potent than imatinib against cells expressing wild-type Bcr-Abl, and that dasatinib is active against 18 of 19 Bcr-Abl mutations known to cause imatinib resistance. Phase I clinical data show that dasatinib is well tolerated and highly effective for the treatment of imatinib-resistant/ imatinib-intolerant chronic myelogenous leukemia (CML) and Philadelphia chromosome -positive acute lymphoblastic leukemia. However, the molecular mechanism of action of dasatinib is not fully understood. In this study, we confirm that dasatinib inhibits tyrosine phosphorylation of SFKs, including Src, Hck, and Lyn, in K562 human CML cells. Significantly, downstream signal transducer and activator of transcription 5 (Stat5) signaling is also blocked by dasatinib as shown by decreases in levels of phosphorylated Stat5 and Stat5 DNA-binding activities. In addition, dasatinib down-regulates expression of Stat5 target genes, including Bcl-x, Mcl-1, and cyclin D1. Consistent with these results, blockade of Stat5 signaling by dasatinib is accompanied by inhibition of cell proliferation and induction of apoptosis. Surprisingly, Stat5 DNA-binding activities are enhanced with increasing cell density, which is associated with resistance to apoptosis by dasatinib. Our findings indicate that inhibition of Stat5 signaling downstream of Bcr-Abl/SFKs contributes to the action of dasatinib, and, conversely, that increasing cell density up-regulates Stat5 activation and confers resistance to dasatinib. Moreover, the level of phosphorylated Stat5 in CML cells represents a mechanistically relevant biomarker for monitoring inhibition of Bcr-Abl signaling by dasatinib in CML patients using convenient immunocytochemical assays.

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Cell-to-cell adhesion modulates Stat3 activity in normal and breast carcinoma cells

Cited by 104 publications

References 55 publications

KIT oncoprotein interactions in gastrointestinal stromal tumors: therapeutic relevance

KIT oncoprotein interactions in gastrointestinal stromal tumors: therapeutic relevance

Microtubule disruption synergizes with oncolytic virotherapy by inhibiting interferon translation and potentiating bystander killing

Dasatinib (BMS-354825) inhibits Stat5 signaling associated with apoptosis in chronic myelogenous leukemia cells

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