Activated Signal Transducer and Activator of Transcription (STAT) 3

Silver, Debra L.; Naora, Honami; Liu, Jinsong; Cheng, Wenjun; Montell, Denise J.

doi:10.1158/0008-5472.can-03-3959

Cited by 229 publications

(95 citation statements)

References 49 publications

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“…Here, we demonstrate that suppression of STAT3 activity impaired the MT network, resulting in the inhibition of T-cell migration. In addition to the multifunctional role of STAT3 in mediating several biological processes, including cell proliferation, differentiation, survival, and motility and promotion of tumor growth (20,43,44), a role of STAT3 is emerging in cell migration, as described in both keratinocytes (23,26) and mouse embryonic fibroblasts (33). In this study, we demonstrate involvement of STAT3 in T-cell migration, suggesting possible wider roles for this molecule in the migratory processes.…”

Section: Discussionsupporting

confidence: 53%

STAT3-Stathmin Interactions Control Microtubule Dynamics in Migrating T-cells

Verma

Dourlat

Davies

et al. 2009

Journal of Biological Chemistry

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T-cell migration is a complex highly coordinated process that involves cell adhesion to the high endothelial venules or to the extracellular matrix by surface receptor/ligand interactions, cytoskeletal rearrangements, and phosphorylation-dependent signaling cascades. The mechanism(s) that regulates T-cell migration is of considerable relevance for understanding the pathogenesis of various diseases, such as chronic inflammatory diseases and cancer metastasis. This study was designed to identify potential involvement of STAT3, a latent transcription factor, in mediating integrin-induced T-cell migration. Using our previously characterized in vitro model for lymphocyte migration, we demonstrate that STAT3 is activated and translocated to the nucleus during the process of active motility of Hut78 T-lymphoma cells triggered via LFA-1. Blocking STAT3 signaling by multiple approaches inhibited LFA-1-induced T-cell locomotion via destabilization of microtubules and post-translational modification of tubulin. Here, we show that STAT3 physically interacts with stathmin to regulate microtubule dynamics in migrating T-cells. These observations strongly indicate that STAT3 is critically important for T-cell migration and associated signaling events.Efficient operation of the adaptive immune system requires migration of T-lymphocytes from the vascular compartment across tissue barriers and through the extracellular matrix. This process involves a series of integrin ligand-receptor interactions (1) that initially retards lymphocyte flow and ultimately leads to arrest and diapedesis across the endothelium (2, 3). T-cells utilize the integrin, lymphocyte function-associated antigen-1 (LFA-1), 3 when migrating in response to chemoattractants across the vasculature into lymph nodes or inflamed tissues (1, 4, 5). By engagement with ligands from the intercellular adhesion molecule group (ICAMs), in particular ICAM-1, LFA-1 also provides a strong adhesive force to promote and stabilize T-cell and antigen-presenting cell conjugate formation. We have demonstrated that LFA-1 transduces a variety of transmembrane signals in crawling T-cells involving protein kinase C activation and cytoskeletal rearrangement (4, 6 -9). However, the exact sequence of downstream integrin-mediated signaling events resulting in cytoskeletal rearrangements and cell locomotion is not fully understood.T-cell migration involves cross-talk between integrins and the cytoskeleton, coordinated changes in the cytoskeleton, and the controlled formation and dispersal of adhesion sites (10). Motile lymphocytes develop trailing extensions, which contain cytoskeletal and signaling elements (11). Microtubules (MTs) are essential components of the cytoskeleton and are important for many aspects of mammalian cell responses, including cell division, growth, migration, and signaling (12)(13)(14). Whereas the actin cytoskeleton provides the driving force at the cell front, the MT network assumes a regulatory function in coordinating rear retraction (15). MT retraction into the ...

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Section: Discussionsupporting

confidence: 53%

STAT3-Stathmin Interactions Control Microtubule Dynamics in Migrating T-cells

Verma

Dourlat

Davies

et al. 2009

Journal of Biological Chemistry

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“…STAT3-deficient keratinocytes showed increased cell adhesiveness and compromised growth factor-inducible cell migration, accompanying with an increased hyperphosphorylation of focal adhesion and its component protein p130cas (Kira et al, 2002). Activated STAT3 in ovarian cancer cells localized to focal adhesions, and depletion of STAT3 with siRNA transfection resulted in the inhibition of migration of ovarian cancer cells (Silver et al, 2004). An intriguing possibility is that STAT3 would become activated in focal adhesions in response to extracellular matrix components and transmit its signals to the nuclei to alter gene expression.…”

Section: Discussionmentioning

confidence: 99%

“…Activation of STAT3 correlates with aggressive behavior of ovarian cancer cells. Activated STAT3 accumulated in focal adhesions as well as nuclei, and blocking STAT3 activity with siRNA transfection resulted in a decrease of ovarian cancer cell migration (Silver et al, 2004). It is likely that activated STAT3 promotes cell migration and invasion through the surrounding extracellular matrix.…”

Section: Introductionmentioning

confidence: 99%

Requirement of STAT3 activation for maximal collagenase-1 (MMP-1) induction by epidermal growth factor and malignant characteristics in T24 bladder cancer cells

et al. 2005

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Signal transducers and activators of transcription (STATs) are latent transcription factors that mediate cytokine-and growth factor-induced transcription. Constitutive activation of STAT3 has been shown in human cancers and transformed cell lines. We report that STAT3, but not STAT1 and STAT5, becomes phosphorylated in response to epidermal growth factor (EGF) and achieves maximal induction of collagenase-1 (MMP-1) transcription by interacting with c-JUN. Phosphorylation of STAT3 protein is biphasic: the first peak within 30 min and the second peak between 4 and 8 h. Association of STAT3 with c-JUN is detected and its constituting STAT3 is increasingly phosphorylated. The STAT and AP-1 elements are necessary for effective induction of MMP-1 promoter by EGF. Mutation of AP-1 element closely located at the STAT site abolishes the binding not only of c-JUN but also of STAT3 to MMP-1 promoter, resulting in the loss of the responsiveness to EGF. By blocking STAT3 activity with the dominant-negative form, we show the requirement of STAT3 for EGF induction of MMP-1 and MMP-10 (stromelysin-2). Furthermore, expression of the dominant-negative STAT3 is sufficient to inhibit the constitutive and EGF-inducible cell migration and invasion and the tumor formation in nude mice. These results demonstrate that STAT3 phosphorylation and its possible interaction with c-JUN are required for the strong responsiveness of MMP-1 to EGF, and STAT3 activation is crucial for exhibition of malignant characteristics in T24 bladder cancer cells.

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“…Moreover, previous studies by Sun et al [66] have showed that sanguinarine reduces prostate cancer cell growth and invasion by the inhibition of STAT3 activation. STAT3 is constitutively active in human prostate cancer metastases and has a key role in the phenomena of tumor cell migration and invasion in different types of cancer [82][83][84] . Since the invasivity and/or metastatic potential of a tumor parallel its maligncy, the above findings indicate that sanguinarine may play a crucial role as a therapeutic agent in anticancer therapy inhibiting the activity of NO synthase, thus suggesting the possibility to use a combination of COX-2 inhibitors and sanguinarine in the treatment of human prostate cancer [28] .…”

Section: Inhibition Of Tumor Cell Invasion By Sanguinarinementioning

confidence: 99%

Antitumor effects of the benzophenanthridine alkaloid sanguinarine: Evidence and perspectives

Gaziano

Moroni

Buè

et al. 2016

WJGO

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Historically, natural products have represented a significant source of anticancer agents, with plant-derived drugs becoming increasingly explored. In particular, sanguinarine is a benzophenanthridine alkaloid obtained from the root of Sanguinaria canadensis , and from other poppy Fumaria species, with recognized anti-microbial, anti-oxidant and anti-inflammatory properties. Recently, increasing evidence that sanguinarine exibits anticancer potential through its capability of inducing apoptosis and/or antiproliferative effects on tumor cells, has been proved. Moreover, its antitumor seems to be due not only to its pro-apoptotic and inhibitory effects on tumor growth, but also to its antiangiogenic and anti-invasive properties. Although the precise mechanisms underlying the antitumor activity of this compound remain not fully understood, in this review we will focus on the most recent findings about the cellular and molecular pathways affected by sanguinarine, together with the rationale of its potential application in clinic. The complex of data currently available suggest the potential application of sanguinarine as an adjuvant in the therapy of cancer, but further pre-clinical studies are needed before such an antitumor strategy can be effectively translated in the clinical practice.

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Activated Signal Transducer and Activator of Transcription (STAT) 3

Cited by 229 publications

References 49 publications

STAT3-Stathmin Interactions Control Microtubule Dynamics in Migrating T-cells

STAT3-Stathmin Interactions Control Microtubule Dynamics in Migrating T-cells

Requirement of STAT3 activation for maximal collagenase-1 (MMP-1) induction by epidermal growth factor and malignant characteristics in T24 bladder cancer cells

Antitumor effects of the benzophenanthridine alkaloid sanguinarine: Evidence and perspectives

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