scholarly journals Attenuation of STAT3 Signaling Cascade by Daidzin Can Enhance the Apoptotic Potential of Bortezomib against Multiple Myeloma

Biomolecules ◽  
2019 ◽  
Vol 10 (1) ◽  
pp. 23 ◽  
Author(s):  
Min Hee Yang ◽  
Sang Hoon Jung ◽  
Arunachalam Chinnathambi ◽  
Tahani Awad Alahmadi ◽  
Sulaiman Ali Alharbi ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Therapeutic Strategy ◽  
Tyrosine Phosphatase ◽  
Signaling Cascade ◽  
Signal Transducer ◽  
Stat3 Signaling ◽  
Anti Cancer ◽  
Prostate Cancers ◽  
Apoptotic Effects ◽  
Transcription 3

Daidzin (DDZ) extracted from Pueraria lobate (Fabaceae) is a widely known phytoestrogen. DDZ can display anti-cancer activities against breast and prostate cancers, but its anti-oncogenic actions in multiple myeloma (MM) cells have not been studied. The signal transducer and activator of transcription 3 (STAT3) can control key processes including proliferation, differentiation, and survival in MM cells. Here, we noted that DDZ abrogated STAT3 activation (both constitutive as well as inducible) at Tyr705 and Ser727 in MM cells. Additionally, DDZ mitigated the phosphorylation of STAT3 upstream Janus-activated kinases (JAK1/2) and c-Src kinases. Pervanadate (tyrosine phosphatase blocker) exposure altered the DDZ-induced inhibition of STAT3 activation, thus affecting the action of this phytoestrogen on apoptosis. Moreover, DDZ impeded proliferation and augmented the apoptotic effects of bortezomib (Bor) in MM cells. Overall, the data indicate that DDZ may act as a potent suppressor of STAT3 signaling cascade, and the co-treatment of DDZ and Bor could be a promising therapeutic strategy, specifically in MM.

scholarly journals STAT3 pathway as a molecular target for resveratrol in breast cancer treatment

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Zeynab Kohandel ◽  
Tahereh Farkhondeh ◽  
Michael Aschner ◽  
Ali Mohammad Pourbagher-Shahri ◽  
Saeed Samarghandian
Keyword(s):  
Breast Cancer ◽  
Cancer Progression ◽  
Breast Cancer Treatment ◽  
Signal Transducer ◽  
Therapeutic Targeting ◽  
Stat3 Signaling ◽  
Naturally Occurring ◽  
Anti Cancer ◽  
Anti Oxidant ◽  
Transcription 3

AbstractSignal transducer and activator of transcription 3 (STAT3) induces breast cancer malignancy. Recent clinical and preclinical studies have demonstrated an association between overexpressed and activated STAT3 and breast cancer progression, proliferation, metastasis, and chemoresistance. Resveratrol (RES), a naturally occurring phytoalexin, has demonstrated anti-cancer activity in several disease models. Furthermore, RES has also been shown to regulate the STAT3 signaling cascade via its anti-oxidant and anti-inflammatory effects. In the present review, we describe the STAT3 cascade signaling pathway and address the therapeutic targeting of STAT3 by RES as a tool to mitigate breast cancer.

scholarly journals Ponatinib Inhibits Multiple Signaling Pathways Involved in STAT3 Signaling and Attenuates Colorectal Tumor Growth

Cancers ◽  
2018 ◽  
Vol 10 (12) ◽  
pp. 526 ◽  
Author(s):  
Fiona Tan ◽  
Tracy Putoczki ◽  
Jieqiong Lou ◽  
Elizabeth Hinde ◽  
Frédéric Hollande ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Therapeutic Strategy ◽  
Acquired Resistance ◽  
Janus Kinase ◽  
Signal Transducer ◽  
Stat3 Signaling ◽  
Multiple Signaling ◽  
Transcription 3

Signal transducer and activator of transcription 3 (STAT3) signaling is a major driver of colorectal cancer (CRC) growth, however therapeutics, which can effectively target this pathway, have so far remained elusive. Here, we performed an extensive screen for STAT3 inhibitors among a library of 1167 FDA-approved agents, identifying Ponatinib as a lead candidate. We found that Ponatinib inhibits STAT3 activity driven by EGF/EGFR, IL-6/IL-6R and IL-11/IL-11R, three major ligand/receptor systems involved in CRC development and progression. Ponatinib was able to inhibit CRC migration and tumor growth in vivo. In addition, Ponatinib displayed a greater ability to inhibit STAT3 activity and mediated superior anti-proliferative efficacy compared to five FDA approved SRC and Janus Kinase (JAK) inhibitors. Finally, long-term exposure of CRC cells to Ponatinib, Dasatinib and Bosutinib resulted in acquired resistance to Dasatinib and Bosutinib occurring within six weeks. However, acquired resistance to Ponatinib was observed after long-term exposure of >4 months. Overall, our results identify a novel anti-STAT3 property of Ponatinib and thus, Ponatinib offers a potential therapeutic strategy for CRC.

scholarly journals HDAC6-Selective Inhibitor Overcomes Bortezomib Resistance in Multiple Myeloma

2021 ◽  
Vol 22 (3) ◽  
pp. 1341
Author(s):  
Sang Wu Lee ◽  
Soo-Keun Yeon ◽  
Go Woon Kim ◽  
Dong Hoon Lee ◽  
Yu Hyun Jeon ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Nuclear Factor Kappa B ◽  
Selective Inhibitor ◽  
Signal Transducer ◽  
Histone Deacetylase 6 ◽  
Cell Growth Inhibition ◽  
Cancer Cell Growth ◽  
Extracellular Signal ◽  
Hdac6 Inhibitor ◽  
Transcription 3

Although multiple myeloma (MM) patients benefit from standard bortezomib (BTZ) chemotherapy, they develop drug resistance, resulting in relapse. We investigated whether histone deacetylase 6 (HDAC6) inhibitor A452 overcomes bortezomib resistance in MM. We show that HDAC6-selective inhibitor A452 significantly decreases the activation of BTZ-resistant markers, such as extracellular signal-regulated kinases (ERK) and nuclear factor kappa B (NF-κB), in acquired BTZ-resistant MM cells. Combination treatment of A452 and BTZ or carfilzomib (CFZ) synergistically reduces BTZ-resistant markers. Additionally, A452 synergizes with BTZ or CFZ to inhibit the activation of NF-κB and signal transducer and activator of transcription 3 (STAT3), resulting in decreased expressions of low-molecular-mass polypeptide 2 (LMP2) and LMP7. Furthermore, combining A452 with BTZ or CFZ leads to synergistic cancer cell growth inhibition, viability decreases, and apoptosis induction in the BTZ-resistant MM cells. Overall, the synergistic effect of A452 with CFZ is more potent than that of A452 with BTZ in BTZ-resistant U266 cells. Thus, our findings reveal the HDAC6-selective inhibitor as a promising therapy for BTZ-chemoresistant MM.

scholarly journals KDM3A histone demethylase functions as an essential factor for activation of JAK2−STAT3 signaling pathway

2018 ◽  
Vol 115 (46) ◽  
pp. 11766-11771 ◽  
Author(s):  
Hyunkyung Kim ◽  
Dongha Kim ◽  
Seon Ah Choi ◽  
Chang Rok Kim ◽  
Se Kyu Oh ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Therapeutic Strategy ◽  
Transcriptional Coactivator ◽  
Essential Factor ◽  
Stat3 Signaling ◽  
Lysine Specific Demethylase ◽  
Tyrosine Kinase 2 ◽  
Stat3 Signaling Pathway ◽  
Janus Tyrosine Kinase 2 ◽  
Transcription 3

Janus tyrosine kinase 2 (JAK2)−signal transducer and activator of transcription 3 (STAT3) signaling pathway is essential for modulating cellular development, differentiation, and homeostasis. Thus, dysregulation of JAK2−STAT3 signaling pathway is frequently associated with human malignancies. Here, we provide evidence that lysine-specific demethylase 3A (KDM3A) functions as an essential epigenetic enzyme for the activation of JAK2−STAT3 signaling pathway. KDM3A is tyrosine-phosphorylated by JAK2 in the nucleus and functions as a STAT3-dependent transcriptional coactivator. JAK2−KDM3A signaling cascade induced by IL-6 leads to alteration of histone H3K9 methylation as a predominant epigenetic event, thereby providing the functional and mechanistic link between activation of JAK2−STAT3 signaling pathway and its epigenetic control. Together, our findings demonstrate that inhibition of KDM3A phosphorylation could be a potent therapeutic strategy to control oncogenic effect of JAK2−STAT3 signaling pathway.

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.

scholarly journals Targeting STAT3 in Cancer Immunotherapy

2020 ◽  
Vol 19 (1) ◽  
Author(s):  
Sailan Zou ◽  
Qiyu Tong ◽  
Bowen Liu ◽  
Wei Huang ◽  
Yan Tian ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Therapeutic Strategy ◽  
Current Status ◽  
Therapeutic Approaches ◽  
Oncogenic Signaling ◽  
Stat3 Signaling ◽  
Stat3 Signaling Pathway ◽  
Oncogenic Signaling Pathways ◽  
Transcription 3 ◽  
Cancerous Cells

Abstract As a point of convergence for numerous oncogenic signaling pathways, signal transducer and activator of transcription 3 (STAT3) is central in regulating the anti-tumor immune response. STAT3 is broadly hyperactivated both in cancer and non-cancerous cells within the tumor ecosystem and plays important roles in inhibiting the expression of crucial immune activation regulators and promoting the production of immunosuppressive factors. Therefore, targeting the STAT3 signaling pathway has emerged as a promising therapeutic strategy for numerous cancers. In this review, we outline the importance of STAT3 signaling pathway in tumorigenesis and its immune regulation, and highlight the current status for the development of STAT3-targeting therapeutic approaches. We also summarize and discuss recent advances in STAT3-based combination immunotherapy in detail. These endeavors provide new insights into the translational application of STAT3 in cancer and may contribute to the promotion of more effective treatments toward malignancies.

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