scholarly journals Role of STAT3 in Cancer Metastasis and Translational Advances

2013 ◽  
Vol 2013 ◽  
pp. 1-15 ◽  
Author(s):  
Mohammad Zahid Kamran ◽  
Prachi Patil ◽  
Rajiv P. Gude
Keyword(s):  
Cancer Metastasis ◽  
Cellular Proliferation ◽  
Nuclear Translocation ◽  
Signal Transducer ◽  
Surface Receptors ◽  
Physiological Conditions ◽  
Stat3 Signaling ◽  
Tumor Growth And Metastasis ◽  
Transcription 3

Signal transducer and activator of transcription 3 (STAT3) is a latent cytoplasmic transcription factor, originally discovered as a transducer of signal from cell surface receptors to the nucleus. It is activated by tyrosine phosphorylation at position 705 leading to its dimerization, nuclear translocation, DNA binding, and activation of gene transcription. Under normal physiological conditions, STAT3 activation is tightly regulated. However, compelling evidence suggests that STAT3 is constitutively activated in many cancers and plays a pivotal role in tumor growth and metastasis. It regulates cellular proliferation, invasion, migration, and angiogenesis that are critical for cancer metastasis. In this paper, we first describe the mechanism of STAT3 regulation followed by how STAT3 is involved in cancer metastasis, then we summarize the various small molecule inhibitors that inhibit STAT3 signaling.

scholarly journals Inhibition of IL-13 and IL-13Rα2 Expression by IL-32θ in Human Monocytic Cells Requires PKCδ and STAT3 Association

2019 ◽  
Vol 20 (8) ◽  
pp. 1949 ◽  
Author(s):  
Thu-Huyen Pham ◽  
Yesol Bak ◽  
Jae-Wook Oh ◽  
Jingi Hong ◽  
Seungyeoun Lee ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Nuclear Translocation ◽  
Inhibitory Effect ◽  
Additive Effects ◽  
Signal Transducer ◽  
Monocytic Cells ◽  
Kinase C ◽  
Direct Association ◽  
Transcription 3

Interleukin (IL)-32θ, a newly identified IL-32 isoform, has been reported to exert pro-inflammatory effects through the association with protein kinase C delta (PKCδ). In this study, we further examined the effects of IL-32θ on IL-13 and IL-13Rα2 expression and the related mechanism in THP-1 cells. Upon stimulating IL-32θ-expressing and non-expressing cells with phorbol 12-myristate 13-acetate (PMA), the previous microarray analysis showed that IL-13Rα2 and IL-13 mRNA expression were significantly decreased by IL-32θ. The protein expression of these factors was also confirmed to be down-regulated. The nuclear translocation of transcription factors STAT3 and STAT6, which are necessary for IL-13Rα2 and IL-13 promoter activities, was suppressed by IL-32θ. Additionally, a direct association was found between IL-32θ, PKCδ, and signal transducer and activator of transcription 3 (STAT3), but not STAT6, revealing that IL-32θ might act mainly through STAT3 and indirectly affect STAT6. Moreover, the interaction of IL-32θ with STAT3 requires PKCδ, since blocking PKCδ activity eliminated the interaction and consequently limited the inhibitory effect of IL-32θ on STAT3 activity. Interfering with STAT3 or STAT6 binding by decoy oligodeoxynucleotides (ODNs) identified that IL-32θ had additive effects with the STAT3 decoy ODN to suppress IL-13 and IL-13Rα2 mRNA expression. Taken together, our data demonstrate the intracellular interaction of IL-32θ, PKCδ, and STAT3 to regulate IL-13 and IL-13Rα2 synthesis, supporting the role of IL-32θ as an inflammatory modulator.

scholarly journals An Electrophilic Deguelin Analogue Inhibits STAT3 Signaling in H-Ras-Transformed Human Mammary Epithelial Cells: The Cysteine 259 Residue as a Potential Target

Biomedicines ◽  
2020 ◽  
Vol 8 (10) ◽  
pp. 407 ◽  
Author(s):  
Sung-Jun Hong ◽  
Jin-Tae Kim ◽  
Su-Jung Kim ◽  
Nam-Chul Cho ◽  
Kyeojin Kim ◽  
...  
Keyword(s):  
Stromal Cells ◽  
Transcriptional Activity ◽  
Nuclear Translocation ◽  
Mammary Epithelial Cells ◽  
Mammary Epithelial ◽  
Transformed Cells ◽  
Signal Transducer ◽  
Stat3 Signaling ◽  
Human Mammary Epithelial ◽  
Transcription 3

Signal transducer and activator of transcription 3 (STAT3) is a point of convergence for numerous oncogenic signals that are often constitutively activated in many cancerous or transformed cells and some stromal cells in the tumor microenvironment. Persistent STAT3 activation in malignant cells stimulates proliferation, survival, angiogenesis, invasion, and tumor-promoting inflammation. STAT3 undergoes activation through phosphorylation on tyrosine 705, which facilitates its dimerization. Dimeric STAT3 translocates to the nucleus, where it regulates the transcription of genes involved in cell proliferation, survival, etc. In the present study, a synthetic deguelin analogue SH48, discovered by virtual screening, inhibited the phosphorylation, nuclear translocation, and transcriptional activity of STAT3 in H-ras transformed human mammary epithelial MCF-10A cells (MCF10A-ras). We speculated that SH48 bearing an α,β-unsaturated carbonyl group could interact with a thiol residue of STAT3, thereby inactivating this transcription factor. Non-electrophilic analogues of SH48 failed to inhibit STAT3 activation, lending support to the above supposition. By utilizing a biotinylated SH48, we were able to demonstrate the complex formation between SH48 and STAT3. SH48 treatment to MCF10A-ras cells induced autophagy, which was verified by staining with a fluorescent acidotropic probe, LysoTracker Red, as well as upregulating the expression of LC3II and p62. In conclusion, the electrophilic analogue of deguelin interacts with STAT3 and inhibits its activation in MCF10A-ras cells, which may account for its induction of autophagic death.

scholarly journals Functional Potentiation of Leptin-Signal Transducer and Activator of Transcription 3 Signaling by the Androgen Receptor

Endocrinology ◽  
2008 ◽  
Vol 149 (12) ◽  
pp. 6028-6036 ◽  
Author(s):  
WuQiang Fan ◽  
Toshihiko Yanase ◽  
Yoshihiro Nishi ◽  
Seiichi Chiba ◽  
Taijiro Okabe ◽  
...  
Keyword(s):  
Androgen Receptor ◽  
Nuclear Translocation ◽  
Steroid Hormone Receptors ◽  
Signal Transducer ◽  
Male Mice ◽  
Wild Type ◽  
Stat3 Signaling ◽  
Transcription 3 ◽  
Arcuate Neurons

Hypogonadism is associated with increased fat mass and dysregulation of metabolic homeostasis in men. Our previous study revealed that androgen receptor (AR)-null male mice (ARL-/Y) develop late-onset obesity and are leptin-resistant. The present study evaluated how hypothalamic AR contributes to central leptin-signal transducer and activator of transcription 3 (STAT3) signaling. We evaluated leptin action in wild-type and ARL-/Y mice, the anatomic co-relationship between AR and leptin signaling in the hypothalamus, and the effects of AR on leptin-mediated STAT3 transactivation and nuclear translocation. AR deletion in male mice results in a weaker leptin-induced suppression of food intake and body weight drop even before the onset of overt obesity. In wild-type male but not female mice, AR was highly expressed in various hypothalamic nuclei that also expressed the long-form leptin receptor (OBRB) and co-resided with OBRB directly in the arcuate neurons. In vitro, AR significantly enhanced STAT3-mediated transcription of leptin target genes including POMC and SOCS3. This effect relied on the AR N-terminal activation function-1 (AF-1) domain and was specific to AR in that none of the other sex steroid hormone receptors tested showed similar effects. AR enhanced the low concentrations of leptin-induced STAT3 nuclear translocation in vitro, and ARL-/Y mice receiving leptin had impaired STAT3 nuclear localization in the arcuate neurons. These findings indicate that AR in the hypothalamus functions as a regulator of central leptin-OBRB-STAT3 signaling and has a physiological role in energy homeostasis and metabolic regulation in male mice.

The Role of STAT3 Signaling in Different Types of Cancers: A Comprehensive Review

2020 ◽  
Vol 16 (3) ◽  
pp. 189-198
Author(s):  
Kaviarasan Lakshmanan ◽  
Gowramma Byran ◽  
Sravanthi Bandlamudi ◽  
Praveen Thaggikuppe Krishnamurthy
Keyword(s):  
Cancer Progression ◽  
Myeloid Leukemia ◽  
Inflammatory Responses ◽  
Vital Role ◽  
Signal Transducer ◽  
Stat3 Signaling ◽  
Solid Malignancies ◽  
Different Types ◽  
Tumor Growth And Metastasis

Signal transducer and activator of transcription (STAT3) is an important transcription factor capable of mediating or even driving cancer progression through hyperactivation or gain-offunction mutations. It plays a key role in regulating host immune and inflammatory responses and in the pathogenesis of many cancers. However, compelling evidence suggests that STAT3 is constitutively activated in many cancers and plays a vital role in tumor growth and metastasis. Hyperactive STAT3 is also implicated in various hematopoietic and solid malignancies, such as chronic and acute myeloid leukemia, melanoma or prostate cancer. The classical understanding of STAT functions is linked to their phosphorylated parallel dimer conformation, in which they induce gene transcription. In this review, we discuss the functions and the roles of STAT3 signal in various types of cancers.

The Role of Signal Transducer and Activator of Transcription 3 (Stat3) in Stretch Injury to Bladder Smooth Muscle Cells

2007 ◽  
Vol 3 ◽  
pp. S35
Author(s):  
Sarel Halachmi ◽  
Karen Aitken ◽  
Martha Szybowska ◽  
Nesrin Sabha ◽  
Shariff Dessouki ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Muscle Cells ◽  
Signal Transducer ◽  
Bladder Smooth Muscle ◽  
Stretch Injury ◽  
Transcription 3

Uterine epithelial LIF receptors contribute to implantation chamber formation in blastocyst attachment

Endocrinology ◽  
2021 ◽  
Author(s):  
Yamato Fukui ◽  
Yasushi Hirota ◽  
Tomoko Saito-Fujita ◽  
Shizu Aikawa ◽  
Takehiro Hiraoka ◽  
...  
Keyword(s):  
Hormone Receptor ◽  
Leukemia Inhibitory Factor ◽  
Ovarian Hormones ◽  
Signal Transducer ◽  
Blastocyst Implantation ◽  
Implantation Process ◽  
Uterine Glands ◽  
Transcription 3

Abstract Recent studies have demonstrated that the formation of an implantation chamber composed of a uterine crypt, an implantation-competent blastocyst, and uterine glands is a critical step in blastocyst implantation in mice. Leukemia inhibitory factor (LIF) activates signal transducer and activator of transcription 3 (STAT3) precursors via uterine LIF receptors (LIFRs), allowing successful blastocyst implantation. Our recent study revealed that the role of epithelial STAT3 is different from that of stromal STAT3. However, both are essential for blastocyst attachment, suggesting the different roles of epithelial and stromal LIFR in blastocyst implantation. However, how epithelial and stromal LIFR regulate the blastocyst implantation process remains unclear. To investigate the roles of LIFR in the uterine epithelium and stroma, we generated Lifr-floxed/lactoferrin (Ltf)-iCre (Lifr eKO) and Lifr-floxed/anti-Mullerian hormone receptor type 2 (Amhr2)-Cre (Lifr sKO) mice with deleted epithelial and stromal LIFR, respectively. Surprisingly, fertility and blastocyst implantation in the Lifr sKO mice were normal despite stromal STAT3 inactivation. In contrast, blastocyst attachment failed, and no implantation chambers were formed in the Lifr eKO mice with epithelial inactivation of STAT3. In addition, normal responsiveness to ovarian hormones was observed in the peri-implantation uteri of the Lifr eKO mice. These results indicate that the epithelial LIFR-STAT3 pathway initiates the formation of implantation chambers, leading to complete blastocyst attachment, and that stromal STAT3 regulates blastocyst attachment without stromal LIFR control. Thus, uterine epithelial LIFR is critical to implantation chamber formation and blastocyst attachment.

scholarly journals The Role of Curcumin in Cancer Treatment

Biomedicines ◽  
2021 ◽  
Vol 9 (9) ◽  
pp. 1086
Author(s):  
Vasiliki Zoi ◽  
Vasiliki Galani ◽  
Georgios D. Lianos ◽  
Spyridon Voulgaris ◽  
Athanasios P. Kyritsis ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Molecular Mechanisms ◽  
Curcuma Longa ◽  
Immune Modulators ◽  
Anticancer Properties ◽  
Stat3 Signaling ◽  
Anticancer Effects ◽  
Transcription 3 ◽  
Light Chain Enhancer

Curcumin is a polyphenol extracted from the rhizomes of the turmeric plant, Curcuma longa which has anti-inflammatory, and anticancer properties. Chronic inflammation is associated with the development of cancer. Curcumin acts on the regulation of various immune modulators, including cytokines, cyclooxygenase-2 (COX-2), and reactive oxygen species (ROS), which partly explains its anticancer effects. It also takes part in the downregulation of growth factors, protein kinases, oncogenic molecules and various signaling pathways, such as nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), c-Jun N-terminal kinase (JNK) and signal transducer and activator of transcription 3 (STAT3) signaling. Clinical trials of curcumin have been completed or are ongoing for various types of cancer. This review presents the molecular mechanisms of curcumin in different types of cancer and the evidence from the most recent clinical trials.

scholarly journals Increased Hypothalamic Signal Transducer and Activator of Transcription 3 Phosphorylation after Hindbrain Leptin Injection

Endocrinology ◽  
2010 ◽  
Vol 151 (4) ◽  
pp. 1509-1519 ◽  
Author(s):  
Marieke Ruiter ◽  
Patricia Duffy ◽  
Steven Simasko ◽  
Robert C. Ritter
Keyword(s):  
Body Weight ◽  
Food Intake ◽  
Fourth Ventricle ◽  
Leptin Receptor ◽  
Janus Kinase ◽  
Signal Transducer ◽  
Solitary Tract ◽  
Stat3 Signaling ◽  
Stat3 Phosphorylation ◽  
Transcription 3

Reduction of food intake and body weight by leptin is attributed largely to its action in the hypothalamus. However, the signaling splice variant of the leptin receptor, LRb, also is expressed in the hindbrain, and leptin injections into the fourth cerebral ventricle or dorsal vagal complex are associated with reductions of feeding and body weight comparable to those induced by forebrain leptin administration. Although these observations suggest direct hindbrain action of leptin on feeding and body weight, the possibility that hindbrain leptin administration also activates the Janus kinase/signal transducer and activator of transcription 3 (STAT3) signaling in the hypothalamus has not been investigated. Confirming earlier work, we found that leptin produced comparable reductions of feeding and body weight when injected into the lateral ventricle or the fourth ventricle. We also found that lateral and fourth ventricle leptin injections produced comparable increases of STAT3 phosphorylation in both the hindbrain and the hypothalamus. Moreover, injection of 50 ng of leptin directly into the nucleus of the solitary tract also increased STAT3 phosphorylation in the hypothalamic arcuate and ventromedial nuclei. Increased hypothalamic STAT3 phosphorylation was not due to elevation of blood leptin concentrations and the pattern of STAT3 phosphorylation did not overlap distribution of the retrograde tracer, fluorogold, injected via the same cannula. Our observations indicate that even small leptin doses administered to the hindbrain can trigger leptin-related signaling in the forebrain, and raise the possibility that STAT3 phosphorylation in the hypothalamus may contribute to behavioral and metabolic changes observed after hindbrain leptin injections.

scholarly journals The Role of Signal Transducer and Activator of Transcription 3 (STAT3) and Its Targeted Inhibition in Hematological Malignancies

Cancers ◽  
2018 ◽  
Vol 10 (9) ◽  
pp. 327 ◽  
Author(s):  
Loukik Arora ◽  
Alan Kumar ◽  
Frank Arfuso ◽  
Wee Chng ◽  
Gautam Sethi
Keyword(s):  
Hematological Malignancies ◽  
Signal Transducer ◽  
Therapeutic Approaches ◽  
Janus Kinases ◽  
Constitutive Activation ◽  
Targeted Inhibition ◽  
Transcription Activators ◽  
Apoptotic Effects ◽  
Transcription 3

Signal transducer and activator of transcription 3 (STAT3), a member of the STAT protein family, can be phosphorylated by receptor-associated Janus kinases (JAKs) in response to stimulation by cytokines and growth factors. It forms homo- or heterodimers that can translocate to the cell nucleus where they act as transcription activators. Constitutive activation of STAT3 has been found to be associated with initiation and progression of various cancers. It can exert proliferative as well as anti-apoptotic effects. This review focuses on the role of STAT3 in pathogenesis i.e., proliferation, differentiation, migration, and apoptosis of hematological malignancies viz. leukemia, lymphoma and myeloma, and briefly highlights the potential therapeutic approaches developed against STAT3 activation pathway.

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