scholarly journals Novel Galiellalactone Analogues Can Target STAT3 Phosphorylation and Cause Apoptosis in Triple-Negative Breast Cancer

Biomolecules ◽  
2019 ◽  
Vol 9 (5) ◽  
pp. 170 ◽  
Author(s):  
Hyejin Ko ◽  
Jong Lee ◽  
Hyun Kim ◽  
Taewoo Kim ◽  
Young Han ◽  
...  
Keyword(s):  
Triple Negative ◽  
Nuclear Translocation ◽  
Breast Cancers ◽  
Stat3 Signaling ◽  
Stat3 Signaling Pathway ◽  
Stat3 Phosphorylation ◽  
Apoptotic Effect ◽  
Potential Strategy ◽  
Induced Apoptosis

Aberrant activation of signal transducer and activator of transcription 3 (STAT3) has been documented in various malignancies including triple-negative breast cancers (TNBCs). The STAT3 transcription factor can regulate the different important hallmarks of tumor cells, and thus, targeting it can be a potential strategy for treating TNBC, for which only limited therapeutic options are available. In this study, we analyzed the possible effect of (-)-galiellalactone and its novel analogues, SG-1709 and SG-1721, and determined whether these agents exerted their antineoplastic effects by suppressing the STAT3 signaling pathway in TNBC cells. The two analogues, SG-1709 and SG-1721, inhibited both constitutive as well as inducible STAT3 phosphorylation at tyrosine 705 more effectively than (-)-galiellalactone, which indicates that the analogues are more potent STAT3 blockers. Moreover, SG-1721 not only inhibited nuclear translocation and DNA binding of STAT3 but also induced apoptosis, and decreased expression of diverse oncogenic proteins. Interestingly, SG-1721 also exhibited an enhanced apoptotic effect when combined with radiotherapy. Furthermore, in vivo administration of SG-1721 significantly attenuated breast xenograft tumor growth via decreasing levels of p-STAT3. Therefore, SG-1721 may be a promising candidate for further application as a pharmacological agent that can target STAT3 protein in treating TNBC.

scholarly journals P01.16 Effects of the STAT3 inhibitors on senescent tumour cells

2020 ◽  
Vol 8 (Suppl 2) ◽  
pp. A16.1-A16
Author(s):  
O Sapega ◽  
R Mikyskova ◽  
K Musilek ◽  
J Bieblova ◽  
Z Hodny ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Czech Republic ◽  
Cell Lines ◽  
Cellular Senescence ◽  
Tumour Cells ◽  
Stat3 Signaling ◽  
Stat3 Signaling Pathway ◽  
Stat3 Phosphorylation

BackgroundCellular senescence is the process of cell proliferation arrest. Premature cellular senescence can be induced by chemotherapy, irradiation and, under certain circumstances, by cytokines. Senescent cells produce a number of secreted proteins and growth factors that may either stimulate or inhibit cell proliferation. One of the major cytokines that play role in regulation of cellular senescence is IL-6. IL-6/STAT3 signaling pathway represent decisive regulatory factors in cellular senescence. The objective of this study was to compare the effects of the STAT3 inhibitors on senescent and proliferative tumour cells. Further, the therapeutic potential of the STAT3 inhibitors was evaluated using murine tumour models.Materials and MethodsIn vitro, as well as in vivo experiments were performed using TC-1 (model for HPV16-associated tumours) TRAMP-C2 (prostate cancer) cell lines. C57Bl/6NCrl mice, 7–8 weeks old, were obtained from Velaz (Prague, Czech Republic). Experimental protocols were approved by the Institutional Animal Care Committee of the Institute of Molecular Genetics (Prague, Czech Republic). STAT3 inhibitors, namely STATTIC, BP-102 (synthesised at the University of Hradec Kralove) and their derivatives were tested for their effects on tumour cells, such as cytotoxicity, ability to inhibit STAT3 phosphorylation, cell proliferation and tumour growth in syngeneic mice.ResultsWe have previously demonstrated that docetaxel-induced senescence in the TC-1 and TRAMP-C2 murine tumour cell lines, which was proved by in vitro (detection of increased p21 expression, positive beta-galactosidase staining, and the typical SASP capable to induce ‘bystander’ senescence), and in vivo experiments, using C57BL/6 mice [1]. Both TC-1 and TRAMP-C2 cells displayed elevated IL-6 secretion and activated STAT3 signaling pathway. Therefore, we tested efficacy of the STAT3 inhibitors on these cell lines. Cytotoxic and STAT3 phosphorylation inhibitory effects of the inhibitors were observed in both proliferating and senescent cells. Antitumor effects of selected inhibitors were evaluated.ConclusionsCollectively, STAT3 is an attractive target for therapeutic approaches in cancer treatment and we can assume that inhibition of the STAT3 pathway can be used for elimination of the pernicious effects of the senescent cells.ReferenceSimova J, Sapega O, Imrichova T, Stepanek I, Kyjacova L, Mikyskova R, Indrova M, Bieblova J, Bubenik J, Bartek J, et al: Tumor growth accelerated by chemotherapy-induced senescent cells is suppressed by treatment with IL-12 producing cellular vaccines. Oncotarget7: 54952–54964, 2016. This work was supported by the research grant No. NV18-05-00562 provided by the Grant Agency of the Ministry of Health of the Czech Republic.Disclosure InformationO. Sapega: None. R. Mikyskova: None. K. Musilek: None. J. Bieblova: None. Z. Hodny: None. M. Reinis: None.

scholarly journals Suppression of STAT3 Phosphorylation and RelA/p65 Acetylation Mediated by MicroRNA134 Plays a Pivotal Role in the Apoptotic Effect of Lambertianic Acid

2019 ◽  
Vol 20 (12) ◽  
pp. 2993 ◽  
Author(s):  
Deok Yong Sim ◽  
Hyo-Jung Lee ◽  
Ji Hoon Jung ◽  
Eunji Im ◽  
Jisung Hwang ◽  
...  
Keyword(s):  
Nuclear Translocation ◽  
Parp Cleavage ◽  
Signal Transducers ◽  
Stat3 Phosphorylation ◽  
Apoptotic Effect ◽  
Lambertianic Acid ◽  
Du145 Cells ◽  
Induced Apoptosis ◽  
Factor Α ◽  
Mcf 7

As p300-mediated RelA/p65 hyperacetylation by signal transducers and activators of transcription 3 (STAT3) is critical for NF-κB activation, in the current study, the apoptotic mechanism of lambertianic acid (LA) was explored in relation to STAT3 phosphorylation and RelA/p65 acetylation in MCF-7, DU145, PC-3, and MDA-MB-453 cells. LA significantly increased the cytotoxicity, sub G 1 population, and the cleavage of poly (ADP-ribose) polymerase (PARP) in MDA-MB-453 or PC-3 cells (STAT3 mutant), more than in the MCF-7 or DU145 cells (STAT3 wild). Consistently, LA inhibited the phosphorylation of STAT3 and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), and disrupted the interaction between p-STAT3, p300, NF-κB, and RelA/p65 acetylation (Ac-RelA/p65) in the MCF-7 and DU145 cells. Also, LA reduced the nuclear translocation of STAT3 and NF-κB via their colocalization, and also suppressed the protein expression of XIAP, survivin, Bcl-2, Bcl-xL, vascular endothelial growth factor (VEGF), Cox-2, c-Myc and mRNA expression of interleukin 6 (IL-6), and tumor necrosis factor-α (TNF-α) in MCF-7 cells. Conversely, IL-6 blocked the ability of LA to suppress the cytotoxicity and PARP cleavage, while the depletion of STAT3 or p300 enhanced the PARP cleavage of LA in the MCF-7 cells. Notably, LA upregulated the level of miRNA134 and so miRNA134 mimic attenuated the expression of pro-PARP, p-STAT3, and Ac-RelA, while the miRNA134 inhibitor reversed the ability of LA to reduce the expression of Ac-RelA and pro-PARP in MCF-7 cells. Overall, these findings suggest that LA induced apoptosis via the miRNA-134 mediated inhibition of STAT3 and RelA/p65 acetylation.

scholarly journals Nitric Oxide-Releasing Drug Glyceryl Trinitrate Targets JAK2/STAT3 Signaling, Migration and Invasion of Triple-Negative Breast Cancer Cells

2021 ◽  
Vol 22 (16) ◽  
pp. 8449
Author(s):  
Sarra Bouaouiche ◽  
Silvia Ghione ◽  
Randa Sghaier ◽  
Olivier Burgy ◽  
Cindy Racoeur ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Glyceryl Trinitrate ◽  
Signaling Pathway ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Migration And Invasion ◽  
Stat3 Signaling ◽  
Stat3 Signaling Pathway ◽  
The Impact

Triple-negative breast cancer (TNBC) is a highly aggressive disease with invasive and metastasizing properties associated with a poor prognosis. The STAT3 signaling pathway has shown a pivotal role in cancer cell migration, invasion, metastasis and drug resistance of TNBC cells. IL-6 is a main upstream activator of the JAK2/STAT3 pathway. In the present study we examined the impact of the NO-donor glyceryl trinitrate (GTN) on the activation of the JAK2/STAT3 signaling pathway and subsequent migration, invasion and metastasis ability of TNBC cells through in vitro and in vivo experiments. We used a subtoxic dose of carboplatin and/or recombinant IL-6 to activate the JAK2/STAT3 signaling pathway and its functional outcomes. We found an inhibitory effect of GTN on the activation of the JAK2/STAT3 signaling, migration and invasion of TNBC cells. We discovered that GTN inhibits the activation of JAK2, the upstream activator of STAT3, and mediates the S-nitrosylation of JAK2. Finally, the effect of GTN (Nitronal) on lung metastasis was investigated to assess its antitumor activity in vivo.

scholarly journals Study on the effect of mongolian medicine qiwei qinggan powder on hepatic fibrosis through JAK2/STAT3 pathway

2021 ◽  
Author(s):  
Jie Liang ◽  
Hongwei Yuan ◽  
Liping Xu ◽  
Feng Wang ◽  
Xiaomei Bao ◽  
...  
Keyword(s):  
Hepatic Fibrosis ◽  
Smooth Muscle Actin ◽  
Janus Kinase ◽  
Alpha Smooth Muscle Actin ◽  
Stat3 Signaling ◽  
Stat3 Signaling Pathway ◽  
Stat3 Phosphorylation ◽  
Histopathological Results

Abstract This research aimed to evaluate the anti-hepatic fibrosis effect and explore the mechanism of Qiwei Qinggan Powder (QGS-7) in vivo and in vitro. Carbon tetrachloride (CCl4)-treated rats and hepatic stellate cells (HSCs) were used. QGS-7 treatment significantly improved the liver function of rats as indicated by decreased serum enzymatic activities of Alanine Aminotransferase (ALT), Aspartate transaminase (AST) and Alkaline Phosphatase (ALP). Meanwhile, the hydroxyproline (HYP) of liver was significantly decreased. Histopathological results indicated that QGS-7 alleviated liver damage and reduced the formation of fibrosis septa. Moreover, QGS-7 significantly attenuated expressions of Alpha smooth muscle actin (α-SMA), Collagen I, Janus kinase 2 (JAK2), phosphorylation-JAK2 (p-JAK2), signal transducer and activator of transcription 3(STAT3), phosphorylation-STAT3 (p-STAT3) in the rat hepatic fibrosis model. QGS-7 inhibited HSCs proliferation and promote it apoptosis. QGS-7 may affect hepatic fibrosis through JAK2/STAT3 signaling pathway, so as to play an anti-hepatic fibrosis role.

Panobinostat Inhibits JAK2/STAT3 Pathway in Multiple Myeloma.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2849-2849
Author(s):  
Giulia Perrone ◽  
Elisabetta Calabrese ◽  
Teru Hideshima ◽  
Gullu Gorgun ◽  
Ikeda Hiroshi ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Signaling Pathway ◽  
Cell Lines ◽  
Research Funding ◽  
Histone Deacetylase Inhibitors ◽  
Nuclear Translocation ◽  
Stat3 Pathway ◽  
Stat3 Signaling ◽  
Stat3 Signaling Pathway ◽  
Stat3 Phosphorylation

Abstract Abstract 2849 Poster Board II-825 Histone deacetylase inhibitors (HDACi) are emerging as a potential therapy for Multiple Myeloma (MM). Their antineoplastic activity depends not only on nucleosomal histone acetylation, but also on direct modulation of non-histone proteins, including p53 or HSP90. Previous studies suggest that histone deacetylases inhibitors modulate Jak2/Stat3 signaling pathway, a cascade mediating tumor cell survival. Here we examine how Panobinostat, a class I-HDAC inhibitor currently in phase I/II clinical trial, can modulate the function of the Jak2/ Stat3 pathway in MM. We first observed that Panobinostat inhibited IL6-induced Stat3 phosphorylation (Tyr705) and Jak2 phosphorylation (Tyr 1007/1008) in MM cell lines ( MM1S and INA6) in a dose- and time- depend fashion, associated with induction of Stat3 acetylation (Lys 685). Since acetylation of Stat3 alters the distribution rather than the functional status of Stat3, we next examined whether Panobinostat altered the nuclear versus cytoplasmic localization of Stat3 in MM cell lines. Although total STAT3 protein level did not change, Panobinostat treatment did trigger decreased nuclear Stat3 phosphorylation, suggesting that Panobinostat blocks Stat3 transcriptional activity. We showed by western blot analysis that the down stream pathway induced by Stat3 (Survivin, Bcl XL, c-Myc) was also down regulated after Panobinostat treatment, further confirming inhibition of STAT3 activity. Take together, our results suggest that Panobinostat inhibits the Jak2/Stat3 pathway by inhibiting STAT3 binding to DNA consensus region, rather than modulating nuclear translocation. To establish the molecular mechanism whereby Panobinostat regulates this pathway, we examined IL6/gp130 receptor, which is upstream in the Jak2 /Stat3 pathway. Panobinostat decreased both cell surface and intracellular gp130 protein expression. Interestingly, Panobinostat also inhibited IL6-induced phosphorylation of gp130, suggesting that it can directly inhibit gp130 activation. Our study therefore suggests a dual mechanism of inhibition of the JAK2/Stat3 pathway induced by Panobinostat via modulation of STAT 3 transcriptional function and gp130 -induced STAT3 activation. Finally, we observed upregulation of the MEK/ERK signaling pathway associated with HDAC inhibition, suggesting that combined blockade of these cascades may be useful. Indeed our preliminary data demonstrate enhanced cytotoxicity in MM cell lines (MM1S and INA6) induced by treatment with combined Panobinostat and MEK inhibitors, even in the presence of bone marrow stromal cells or survival cytokines ( IL6 or IGF). Our study therefore suggests a novel mechanism of action of HDAC inhibitors that provides the rationale for clinical evaluation of novel combinations based upon targeting STAT3 signaling pathway. Disclosures: Anderson: Celgene : Research Funding; Novartis: Research Funding; Millennium: Research Funding.

scholarly journals LLL12B, a small molecule STAT3 inhibitor, induces growth arrest, apoptosis, and enhances cisplatin-mediated cytotoxicity in medulloblastoma cells

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Xiang Chen ◽  
Li Pan ◽  
Jia Wei ◽  
Ruijie Zhang ◽  
Xiaozhi Yang ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Small Molecule ◽  
Single Agent ◽  
Stat3 Signaling ◽  
Molecule Inhibitor ◽  
Stat3 Phosphorylation ◽  
Induced Apoptosis ◽  
Transcription 3

AbstractSignal Transducer and Activator of Transcription 3 (STAT3) is a transcription factor and an oncogene product, which plays a pivotal role in tumor progression. Therefore, targeting persistent STAT3 signaling directly is an attractive anticancer strategy. The aim of this study is to test the efficacy of a novel STAT3 small molecule inhibitor, LLL12B, in suppressing medulloblastoma cells in vitro and tumor growth in vivo. LLL12B selectively inhibited the induction of STAT3 phosphorylation by interleukin-6 but not induction of STAT1 phosphorylation by INF-γ. LLL12B also induced apoptosis in human medulloblastoma cells. In addition, LLL12B exhibited good oral bioavailability in vivo and potent suppressive activity in tumor growth of medulloblastoma cells in vivo. Besides, combining LLL12B with cisplatin showed greater inhibition of cell viability and tumorsphere formation as well as induction of apoptosis comparing to single agent treatment in medulloblastoma cells. Furthermore, LLL12B and cisplatin combination exhibited greater suppression of medulloblastoma tumor growth than monotherapy in vivo. The present study supported that LLL12B is a novel therapeutic agent for medulloblastoma and the combination of LLL12B with a chemotherapeutic agent cisplatin may be an effective approach for medulloblastoma therapy.

scholarly journals The mitotic checkpoint is a targetable vulnerability of carboplatin-resistant triple negative breast cancers

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Stijn Moens ◽  
Peihua Zhao ◽  
Maria Francesca Baietti ◽  
Oliviero Marinelli ◽  
Delphi Van Haver ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative ◽  
Breast Cancer Subtype ◽  
Mitotic Checkpoint ◽  
Breast Cancers ◽  
Checkpoint Kinases ◽  
Xenograft Models ◽  
Potential Strategy ◽  
Shrna Screen ◽  
Resistant Cells

AbstractTriple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype, lacking effective therapy. Many TNBCs show remarkable response to carboplatin-based chemotherapy, but often develop resistance over time. With increasing use of carboplatin in the clinic, there is a pressing need to identify vulnerabilities of carboplatin-resistant tumors. In this study, we generated carboplatin-resistant TNBC MDA-MB-468 cell line and patient derived TNBC xenograft models. Mass spectrometry-based proteome profiling demonstrated that carboplatin resistance in TNBC is linked to drastic metabolism rewiring and upregulation of anti-oxidative response that supports cell replication by maintaining low levels of DNA damage in the presence of carboplatin. Carboplatin-resistant cells also exhibited dysregulation of the mitotic checkpoint. A kinome shRNA screen revealed that carboplatin-resistant cells are vulnerable to the depletion of the mitotic checkpoint regulators, whereas the checkpoint kinases CHEK1 and WEE1 are indispensable for the survival of carboplatin-resistant cells in the presence of carboplatin. We confirmed that pharmacological inhibition of CHEK1 by prexasertib in the presence of carboplatin is well tolerated by mice and suppresses the growth of carboplatin-resistant TNBC xenografts. Thus, abrogation of the mitotic checkpoint by CHEK1 inhibition re-sensitizes carboplatin-resistant TNBCs to carboplatin and represents a potential strategy for the treatment of carboplatin-resistant TNBCs.

scholarly journals TrkA Interacts with and Phosphorylates STAT3 to Enhance Gene Transcription and Promote Breast Cancer Stem Cells in Triple-Negative and HER2-Enriched Breast Cancers

Cancers ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 2340
Author(s):  
Angelina T. Regua ◽  
Noah R. Aguayo ◽  
Sara Abu Jalboush ◽  
Daniel L. Doheny ◽  
Sara G. Manore ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Stem Cells ◽  
Cancer Stem Cells ◽  
Gene Transcription ◽  
Target Genes ◽  
Triple Negative ◽  
Breast Cancer Stem Cells ◽  
Breast Cancers ◽  
Co Activation ◽  
Stat3 Phosphorylation

JAK2–STAT3 and TrkA signaling pathways have been separately implicated in aggressive breast cancers; however, whether they are co-activated or undergo functional interaction has not been thoroughly investigated. Herein we report, for the first time that STAT3 and TrkA are significantly co-overexpressed and co-activated in triple-negative breast cancer (TNBC) and HER2-enriched breast cancer, as shown by immunohistochemical staining and data mining. Through immunofluorescence staining–confocal microscopy and immunoprecipitation–Western blotting, we found that TrkA and STAT3 co-localize and physically interact in the cytoplasm, and the interaction is dependent on STAT3-Y705 phosphorylation. TrkA–STAT3 interaction leads to STAT3 phosphorylation at Y705 by TrkA in breast cancer cells and cell-free kinase assays, indicating that STAT3 is a novel substrate of TrkA. β-NGF-mediated TrkA activation induces TrkA–STAT3 interaction, STAT3 nuclear transport and transcriptional activity, and the expression of STAT3 target genes, SOX2 and MYC. The co-activation of both pathways promotes breast cancer stem cells. Finally, we found that TNBC and HER2-enriched breast cancer with JAK2–STAT3 and TrkA co-activation are positively associated with poor overall metastasis-free and organ-specific metastasis-free survival. Collectively, our study uncovered that TrkA is a novel activating kinase of STAT3, and their co-activation enhances gene transcription and promotes breast cancer stem cells in TNBC and HER2-enriched breast cancer.

scholarly journals CircSOD2 induced epigenetic alteration drives hepatocellular carcinoma progression through activating JAK2/STAT3 signaling pathway

2020 ◽  
Vol 39 (1) ◽  
Author(s):  
Zhongwei Zhao ◽  
Jingjing Song ◽  
Bufu Tang ◽  
Shiji Fang ◽  
Dengke Zhang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Cycle ◽  
Cell Migration ◽  
Real Time ◽  
Signaling Pathway ◽  
Molecular Mechanism ◽  
Stat3 Signaling ◽  
Stat3 Signaling Pathway ◽  
Signaling Axis

Abstract Background Emerging evidence suggests that circular RNAs play critical roles in disease development especially in cancers. Previous genome-wide RNA-seq studies found that a circular RNA derived from SOD2 gene was highly upregulated in hepatocellular carcinoma (HCC), however, the role of circSOD2 in HCC remains largely unknown. Methods The expression profiling of circSOD2 and microRNA in HCC patients were assessed by Real-Time Quantitative Reverse Transcription PCR (qRT-PCR). SiRNA or CRISPR-CAS9 were used to silence gene expression. The biological function of circSOD2 in HCC was investigated using in vitro and in vivo studies including, trans-well cell migration, cell apoptosis, cell cycle, CCK8, siRNA interference, western blots, and xenograft mouse model. The underlying molecular mechanism was determined by Chromatin Immunoprecipitation quantitative real time PCR (ChIP-qPCR), bioinformatic analysis, biotin-pull down, RNA immunoprecipitation, 5-mc DNA pulldown and luciferase assays. Results In accordance with previous sequencing results, here, we demonstrated that circSOD2 was highly expressed in HCC tumor tissues compared with normal liver tissues. Mechanically, we showed that histone writer EP300 and WDR5 bind to circSOD2 promoter and trigger its promoter H3K27ac and H3K4me3 modification, respectively, which further activates circSOD2 expression. SiRNA mediated circSOD2 suppression impaired liver cancer cell growth, cell migration, prohibited cell cycle progression and in vivo tumor growth. By acting as a sponge, circSOD2 inhibits miR-502-5p expression and rescues miR-502-5p target gene DNMT3a expression. As a DNA methyltransferase, upregulated DNMA3a suppresses SOCS3 expression by increasing SOCS3 promoter DNA methylation. This event further accelerates SOCS3 downstream JAK2/STAT3 signaling pathway activation. In addition, we also found that activated STAT3 regulates circSOD2 expression in a feedback way. Conclusion The novel signaling axis circSOD2/miR-502-5p/DNMT3a/JAK2/STAT3/circSOD2 provides a better understanding of HCC tumorigenesis. The molecular mechanism underlying this signaling axis offers new prevention and treatment of HCC.

Sign in / Sign up

Export Citation Format

Share Document