Tris(dibenzylideneacetone)dipalladium(0) (Tris DBA) Abrogates Tumor Progression in Hepatocellular Carcinoma and Multiple Myeloma Preclinical Models by Regulating the STAT3 Signaling Pathway

STAT3 is an oncogenic transcription factor that controls the expression of genes associated with oncogenesis and malignant progression. Persistent activation of STAT3 is observed in human malignancies, including hepatocellular carcinoma (HCC) and multiple myeloma (MM). Here, we have investigated the action of Tris(dibenzylideneacetone) dipalladium 0 (Tris DBA) on STAT3 signaling in HCC and MM cells. Tris DBA decreased cell viability, increased apoptosis, and inhibited IL-6 induced/constitutive activation of STAT3, JAK1, JAK2, and Src in HCC and MM cells. Tris DBA downmodulated the nuclear translocation of STAT3 and reduced its DNA binding ability. It upregulated the expression of SHP2 (protein and mRNA) to induce STAT3 dephosphorylation, and the inhibition of SHP2 reversed this effect. Tris DBA downregulated the expression of STAT3-driven genes, suppressed cell migration/invasion. Tris DBA significantly inhibited tumor growth in xenograft MM and orthotopic HCC preclinical mice models with a reduction in the expression of various prosurvival biomarkers in MM tumor tissues without displaying significant toxicity. Overall, Tris DBA functions as a good inhibitor of STAT3 signaling in preclinical HCC and MM models.

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Tris DBA Abrogates Tumor Progression in Hepatocellular Carcinoma and Multiple Myeloma Preclinical Models by Affecting Multiple Oncogenic Proteins

10.21203/rs.3.rs-100294/v1 ◽

2020 ◽

Author(s):

Loukik Arora ◽

Chakrabhavi Dhananjaya Mohan ◽

Chulwon Kim ◽

Shobith Rangappa ◽

Amudha Deivasigamani ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Multiple Myeloma ◽

Tyrosine Kinases ◽

Nuclear Translocation ◽

Dna Interaction ◽

Stat3 Signaling ◽

Expression Of Genes ◽

Biochemical Assays ◽

Significant Toxicity ◽

Tumor Tissues

Abstract Background: STAT3 is an oncogenic transcription factor that controls the expression of genes associated with proliferation, apoptotic resistance, malignant transformation, and metastasis. Persistent activation of STAT3 is observed in many types of human malignancies including hepatocellular carcinoma (HCC) and multiple myeloma (MM). Methods: Here, we have investigated the action of Tris(dibenzylideneacetone) dipalladium 0 (Tris DBA), a palladium complex on STAT3 signaling cascade in HCC and MM. The cytotoxic and proapoptotic activity of Tris DBA was evaluated by various biochemical assays. The action of Tris DBA on cytokine-induced/constitutive activation of STAT3, non-receptor tyrosine kinases (NRTKs), and expression of STAT3 driven genes was evaluated. Nuclear translocation of STAT3 and its DNA interaction was also studied. The antitumor activity of Tris DBA was investigated in two different preclinical studies namely, xenograft MM and orthotopic HCC mice models.Results: Tris DBA decreased cell viability, increased the apoptosis, and inhibited the activation of STAT3 and NRTKs. Tris DBA downmodulated the nuclear translocation of STAT3 and reduced its DNA binding ability. It upregulated expression of SHP2 (protein and mRNA) to induce STAT3 dephosphorylation and inhibition of SHP2 reversed this effect. It downregulated the expression of STAT3-driven genes and suppressed cell motility. Tris DBA significantly inhibited tumor growth in xenograft MM and orthotopic HCC mice models with reduction in the expression of various prosurvival biomarkers in MM tumor tissues without displaying any significant toxicity. Conclusions: Tris DBA functions as a good inhibitor of STAT3 signaling in preclinical HCC and MM models.

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Panobinostat Inhibits JAK2/STAT3 Pathway in Multiple Myeloma.

Blood ◽

10.1182/blood.v114.22.2849.2849 ◽

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.

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

Journal of Experimental & Clinical Cancer Research ◽

10.1186/s13046-020-01769-7 ◽

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.

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3-Formylchromone Counteracts STAT3 Signaling Pathway by Elevating SHP-2 Expression in Hepatocellular Carcinoma

Biology ◽

10.3390/biology11010029 ◽

2021 ◽

Vol 11 (1) ◽

pp. 29

Author(s):

Chakrabhavi Dhananjaya Mohan ◽

Min Hee Yang ◽

Shobith Rangappa ◽

Arunachalam Chinnathambi ◽

Sulaiman Ali Alharbi ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Signaling Pathway ◽

Tyrosine Kinases ◽

Present Report ◽

Migration And Invasion ◽

Stat3 Signaling ◽

Stat3 Signaling Pathway ◽

Substantial Toxicity ◽

Transcription 3 ◽

Constitutive Phosphorylation

Hepatocellular carcinoma (HCC) is one of the leading cancers that contribute to a large number of deaths throughout the globe. The signal transducer and activator of transcription 3 (STAT3) is a tumorigenic protein that is overactivated in several human malignancies including HCC. In the present report, the effect of 3-formylchromone (3FC) on the STAT3 signaling pathway in the HCC model was investigated. 3FC downregulated the constitutive phosphorylation of STAT3 and non-receptor tyrosine kinases such as JAK1 and JAK2. It also suppressed the transportation of STAT3 to the nucleus and reduced its DNA-binding ability. Pervanadate treatment overrode the 3FC-triggered STAT3 inhibition, and the profiling of cellular phosphatase expression revealed an increase in SHP-2 levels upon 3FC treatment. The siRNA-driven deletion of SHP-2 led to reinstate STAT3 activation. 3FC downmodulated the levels of various oncogenic proteins and decreased CXCL12-driven cell migration and invasion. Interestingly, 3FC did not exhibit any substantial toxicity, whereas it significantly regressed tumor growth in an orthotopic HCC mouse model and abrogated lung metastasis. Overall, 3FC can function as a potent agent that can display antitumor activity by targeting STAT3 signaling in HCC models.

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Physagulide Q suppresses proliferation and induces apoptosis in human hepatocellular carcinoma cells by regulating the ROS-JAK2/Src-STAT3 signaling pathway

RSC Advances ◽

10.1039/c6ra25032g ◽

2017 ◽

Vol 7 (21) ◽

pp. 12793-12804 ◽

Cited By ~ 4

Author(s):

Yan-Wei Yang ◽

Lei Yang ◽

Chao Zhang ◽

Cai-Yun Gao ◽

Ting Ma ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Signaling Pathway ◽

Natural Compound ◽

Carcinoma Cells ◽

Human Hepatocellular Carcinoma ◽

Hepatocellular Carcinoma Cells ◽

Stat3 Signaling ◽

Stat3 Signaling Pathway ◽

Physalis Angulata ◽

Human Hepatocellular Carcinoma Cells

Physagulide Q (PQ), a new natural compound, was isolated from Physalis angulata L. in our laboratory.

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Yu Ping Feng San Exert Anti-Angiogenesis Effects through the Inhibition of TSLP-STAT3 Signaling Pathways in Hepatocellular Carcinoma

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2019/1947156 ◽

2019 ◽

Vol 2019 ◽

pp. 1-16 ◽

Cited By ~ 2

Author(s):

Qin Yuan ◽

Fei Yao ◽

Liang Zhou ◽

Guoqiang Liang ◽

Xiudao Song ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

High Performance ◽

Inhibitory Effect ◽

Tube Formation ◽

Significant Inhibition ◽

Related Factor ◽

Related Factors ◽

Chemotherapy Drugs ◽

Stat3 Signaling ◽

Stat3 Signaling Pathway

Background. Clinically, Yu ping feng san (YPFS) has been extensively used as a medication for treating immune deficiency, and YPFS is combined with chemotherapy drugs to treat cancer, including hepatocellular carcinoma (HCC), lung cancer, and pancreatic cancer. Previous research has shown that YPFS has a therapeutic effect on HCC by improving the immunosuppressive state of the liver cancer microenvironment. The present study aimed to investigate the effect of YPFS on angiogenesis of HCC. Methods. High-performance liquid chromatography (HPLC) was used to certify the composition of YPFS. An orthotopic transplanted model of murine HCC was entrenched. Immunohistochemistry was used to observe the changes of the microvessel density (MVD). The MTT assay was used to detect the cell viability. ELISA was performed to analyze the expression of related factors. Western blot was used to analyze the protein expression. Tube formation assay was used to analyze the anti-angiogenic efficiency. Results. YPFS significantly reduced the tumor volume and weight, thus exerted the growth inhibitory effect. The level of MVD and VEGF was obviously decreased in YPFS-treated HCC-bearing mice, and the YPFS treatment also reduced the VEGF level in Hepa1-6 cells. Further study revealed that the expression of TSLP/TSLPR and p-STAT3/STAT3 was decreased by YPFS. The level of MVD and VEGF and the expression of TSLP/TSLPR and p-STAT3/STAT3 in tumor tissue and Hepa1-6 cells were suppressed by incubation with the anti-TSLP antibody, whereas treatment with the anti-TSLP antibody in YPFS-treated cells did not cause further significant inhibition compared with the cells treated only with YPFS. More importantly, YPFS inhibited proliferation, expression of p-STAT3/STAT3, and tube formation of HUVECs induced by TSLP. Conclusions. These results indicated that YPFS attenuated the activation of the TSLP-STAT3 signaling pathway by inhibiting the immune-related factor-TSLP, thereby inhibiting the formation of hepatic microvessels and exerting an anti-HCC effect.

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