Inhibitory Effects of Tangeretin, a Citrus Peel-Derived Flavonoid, on Breast Cancer Stem Cell Formation through Suppression of Stat3 Signaling

Breast cancer stem cells (BCSCs) are responsible for tumor chemoresistance and recurrence. Targeting CSCs using natural compounds is a novel approach for cancer therapy. A CSC-inhibiting compound was purified from citrus extracts using silica gel, gel filtration and high-pressure liquid chromatography. The purified compound was identified as tangeretin by using nuclear magnetic resonance (NMR). Tangeretin inhibited cell proliferation, CSC formation and tumor growth, and modestly induced apoptosis in CSCs. The frequency of a subpopulation with a CSC phenotype (CD44+/CD24−) was reduced by tangeretin. Tangeretin reduced the total level and phosphorylated nuclear level of signal transducer and activator of transcription 3 (Stat3). Our results in this study show that tangeretin inhibits the Stat3 signaling pathway and induces CSC death, indicating that tangeretin may be a potential natural compound that targets breast cancer cells and CSCs.

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The PAK1-Stat3 Signaling Pathway Activates IL-6 Gene Transcription and Human Breast Cancer Stem Cell Formation

Cancers ◽

10.3390/cancers11101527 ◽

2019 ◽

Vol 11 (10) ◽

pp. 1527 ◽

Cited By ~ 8

Author(s):

Ji-Hyang Kim ◽

Hack Sun Choi ◽

Su-Lim Kim ◽

Dong-Sun Lee

Keyword(s):

Breast Cancer ◽

Signaling Pathway ◽

Cell Formation ◽

Janus Kinase ◽

Mobility Shift ◽

Mammosphere Formation ◽

Jak2 Inhibitor ◽

Stat3 Signaling ◽

Group I ◽

Stat3 Signaling Pathway

Cancer stem cells (CSCs) have unique properties, including self-renewal, differentiation, and chemoresistance. In this study, we found that p21-activated kinase (PAK1) inhibitor (Group I, PAK inhibitor, IPA-3) and inactivator (ivermectin) treatments inhibit cell proliferation and that tumor growth of PAK1-knockout cells in a mouse model is significantly reduced. IPA-3 and ivermectin inhibit CSC formation. PAK1 physically interacts with Janus Kinase 2 (JAK2), and JAK2 inhibitor (TG101209) treatment inhibits mammosphere formation and reduces the nuclear PAK1 protein level. PAK1 interacts with signal transducer and activator of transcription 3 (Stat3), and PAK1 and Stat3 colocalize in the nucleus. We show through electrophoretic mobility shift assay (EMSA), chromatin immunoprecipitation (ChIP), and reporter assays that the PAK1/Stat3 complex binds to the IL-6 promoter and regulates the transcription of the IL-6 gene. Inhibition of PAK1 and JAK2 in mammospheres reduces the nuclear pStat3 and extracellular IL-6 levels. PAK1 inactivation inhibits CSC formation by decreasing pStat3 and extracellular IL-6 levels. Our results reveal that JAK2/PAK1 dysregulation inhibits the Stat3 signaling pathway and CSC formation, the PAK1/Stat3 complex regulates IL-6 gene expression, PAK1/Stat3 signaling regulates CSC formation, and PAK1 may be an important target for treating breast cancer.

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A Sesquiterpenoid from Farfarae Flos Induces Apoptosis of MDA-MB-231 Human Breast Cancer Cells through Inhibition of JAK–STAT3 Signaling

Biomolecules ◽

10.3390/biom9070278 ◽

2019 ◽

Vol 9 (7) ◽

pp. 278 ◽

Cited By ~ 7

Author(s):

Hyeri Jang ◽

Hyejin Ko ◽

Kwangho Song ◽

Yeong Kim

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Target Genes ◽

Intraperitoneal Administration ◽

Breast Cancers ◽

Anticancer Effect ◽

Stat3 Signaling ◽

Induced Apoptosis ◽

Transcription 3 ◽

Anticancer Compound

Triple-negative breast cancers (TNBCs) are hard-to-treat breast tumors with poor prognosis, which need to be treated by chemotherapy. Signal transducer and activator of transcription 3 (STAT3) is a transcription factor involved in proliferation, metastasis, and invasion of cancer cells. Therefore, research on searching for promising compounds with metabolism that suppress phosphorylation or transcription of STAT3 in TNBC cells is important. Farfarae Flos is well known as a traditional medicine for treating inflammation. However, few studies have shown that sesquiterpenoids from Farfarae Flos have an anticancer effect. In this study, efficient separation methods and an MTT assay were conducted to isolate an anticancer compound from Farfarae Flos against TNBC MDA-MB-231 cells. Here, 7β-(3-Ethyl-cis-crotonoyloxy)-1α-(2-methylbutyryloxy)-3,14-dehydro-Z-notonipetranone (ECN), a compound isolated from Farfarae Flos showed a potent cytotoxic effect on MDA-MB-231 cells. ECN inhibited JAK–STAT3 signaling and suppressed the expression of STAT3 target genes. In addition, ECN induced apoptosis through both extrinsic and intrinsic pathways. Furthermore, we investigated that ECN inhibited the growth of tumors by intraperitoneal administration in mice injected with MDA-MB-231 cells. Therefore, ECN can be an effective chemotherapeutic agent for breast cancer treatment.

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Rho GTPase Activating Protein 24 (ARHGAP24) Regulates the Anti-Cancer Activity of Sorafenib Against Breast Cancer MDA-MB-231 Cells via the Signal Transducer and Activator of Transcription 3 (STAT3) Signaling Pathway

Medical Science Monitor ◽

10.12659/msm.911394 ◽

2018 ◽

Vol 24 ◽

pp. 8669-8677 ◽

Cited By ~ 2

Author(s):

Xianping Dai ◽

Feng Geng ◽

Jiale Dai ◽

Mengshun Li ◽

Ming Liu

Keyword(s):

Breast Cancer ◽

Signaling Pathway ◽

Rho Gtpase ◽

Signal Transducer ◽

Gtpase Activating Protein ◽

Stat3 Signaling ◽

Stat3 Signaling Pathway ◽

Anti Cancer ◽

Transcription 3 ◽

Cancer Activity

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Tissue Microarray Based Investigation of Stat3 Signaling Pathway in Breast Cancer

10.21236/ada425703 ◽

2004 ◽

Author(s):

Marisa Dolled-Filhart

Keyword(s):

Breast Cancer ◽

Signaling Pathway ◽

Tissue Microarray ◽

Stat3 Signaling ◽

Stat3 Signaling Pathway

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Rational drug design of benzothiazole-based derivatives as potent signal transducer and activator of transcription 3 (STAT3) signaling pathway inhibitors

European Journal of Medicinal Chemistry ◽

10.1016/j.ejmech.2021.113333 ◽

2021 ◽

Vol 216 ◽

pp. 113333

Author(s):

Dingding Gao ◽

Nan Jin ◽

Yixian Fu ◽

Yueyue Zhu ◽

Yujie Wang ◽

...

Keyword(s):

Drug Design ◽

Signaling Pathway ◽

Rational Drug Design ◽

Signal Transducer ◽

Stat3 Signaling ◽

Stat3 Signaling Pathway ◽

Rational Drug ◽

Transcription 3

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

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1805662115 ◽

2018 ◽

Vol 115 (46) ◽

pp. 11766-11771 ◽

Cited By ~ 10

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.

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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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Targeting STAT3 in Cancer Immunotherapy

Molecular Cancer ◽

10.1186/s12943-020-01258-7 ◽

2020 ◽

Vol 19 (1) ◽

Cited By ~ 2

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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