Capsazepine inhibits JAK/STAT3 signaling, tumor growth, and cell survival in prostate cancer

Lee, Jong Hyun; Chulwon, Kim; Baek, Seung Ho; Ko, Jeong‐Hyeon; Lee, Seok-Geun; Yang, Woong Mο; Um, Jae‐Young; Sethi, Gautam; Ahn, Kwang Seok

doi:10.18632/oncotarget.10775

Cited by 110 publications

(90 citation statements)

References 35 publications

(36 reference statements)

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“…Signal transducer and activator of transcription 3 (STAT3) is a member of the STAT transcription factor family, which has been associated with various biological processes, including cell growth, survival and metastasis (10). STAT3 mainly exists…”

Section: Introductionmentioning

confidence: 99%

Gallic acid has anticancer activity and enhances the anticancer effects of cisplatin in non‑small cell lung cancer A549 cells via the JAK/STAT3 signaling pathway

Zhang¹,

Ma²,

Wu³

et al. 2019

Oncol Rep

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Gallic acid (3,4,5-trihydroxybenzoic acid; GA), a plant-derived natural phenolic compound, has been reported to prevent the development and progression of various types of cancers. However, there has been little elaboration of the anticancer effects and underlying mechanisms of GA alone and/or in combination with cisplatin in non-small cell lung cancer (NSCLC). The aim of the present study was to investigate the anticancer effects of GA on NSCLC A549 cells and its auxiliary effects on the anticancer activity of cisplatin. The results revealed that GA inhibited the proliferation and induced the apoptosis of NSCLC A549 cells in dose-and time-dependent manners, which was associated with upregulated B-cell lymphoma 2 (Bcl-2)-associated X protein (Bax) and downregulated Bcl-2. Notably, the results also indicated that GA enhanced the anticancer effects of cisplatin in the inhibition of cancer cell proliferation and the induction of cell apoptosis following elevated Bax expression and suppressed Bcl-2 expression. Furthermore, the results of the present study also demonstrated that GA exerted independent anticancer effects on NSCLC A549 cells, and facilitated the anticancer effects of cisplatin by modulating the JAK/STAT3 signaling pathway and downstream apoptotic molecules. These results may serve as a rationale for further basic studies and preclinical investigations on the anticancer effects of GA and its auxiliary effects on cisplatin function in human NSCLC.

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Section: Introductionmentioning

confidence: 99%

Gallic acid has anticancer activity and enhances the anticancer effects of cisplatin in non‑small cell lung cancer A549 cells via the JAK/STAT3 signaling pathway

Zhang¹,

Ma²,

Wu³

et al. 2019

Oncol Rep

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“…Among the inflammatory signaling pathways that are related to tumor development, the phosphorylation of signal transducer and activator of transcription (STAT3) plays a key role [7]. STAT3, an oncogenic transcription factor, is usually constitutively active in many human cancers, such as prostate cancer, breast cancer and several other malignancies [8-10]. STAT3 has been considered a target for anti-cancer therapy because it plays an important role in tumor cell survival and proliferation [11].…”

Section: Introductionmentioning

confidence: 99%

IL-17 Activates the IL-6/STAT3 Signal Pathway in the Proliferation of Hepatitis B Virus-Related Hepatocellular Carcinoma

Luo

Wang

et al. 2017

Cell Physiol Biochem

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Background/Aims: We performed this study to determine the role of IL-17 in the immune microenvironment of hepatitis B virus- (HBV-) related hepatocellular carcinoma (HCC). Methods: HepG2 cells were treated with IL-17, STAT3 inhibitor S31-201 or IL-6 neutralizing monoclonal antibody (IL-6 mAb). Cell proliferation and migration were compared using the Cell Counting kit-8 (CCK-8) and Transwell assays, respectively. Real-time quantitative PCR (RT-qPCR), Western Blot, ELISA, immunofluorescence and histological staining were used for determining the expression levels of IL-17, IL-6, MCP-1, CCL5, VEGF, STAT3 and p-STAT3. HCC xenograft models were constructed in wild type and IL-17 knockout mice to clarify the effects of IL-17 on HCC in vivo. Results: Exogenous IL-17 enhanced the proliferation and migration of HepG2 cells, and it activated the phosphorylation of STAT3. RT-qPCR and ELISA showed that IL-17 promoted the expression of IL-6. The CCK-8 and Transwell assays showed that S31-201 or IL-6 mAb remarkably reversed the promotion effects of proliferation and migration by exogenous IL-17 in HepG2 cells. Additionally, IL-6 could promote the phosphorylation of STAT3, while IL-6 mAb acted as an inhibitor, and exogenous IL-17 could neutralize the inhibitory effects of IL-6 mAb. In vivo, compared to the wild type mice, the tumor volume, weight, density and size were decreased in IL-17 knockout mice. Additionally, the expression levels of p-STAT3, IL-6, MCP-1, CCL5 and VEGF decreased in IL-17 knockout mice. Conclusions: IL-17 can enhance the proliferation of HepG2 cells in vitro and in vivo via activating the IL-6/STAT3 pathway. Therefore, the IL-17/IL-6/STAT3 signaling pathway is a potential therapeutic target for HBV-related HCC.

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“…The stimulation of transmembrane receptors by cytokines (IL-6 family members) or growth factors (EGF and HGF) lead to the activation of a non-receptor tyrosine kinase, such as Src and Janus kinase (JAK). The activated upstream kinases phosphorylate STAT3 at Tyr705 to undergo dimerization, and translocation into nucleus to transcribe the genes that are involved in proliferation (cyclin D1/E1), inflammation (COX2, IL-1/6 and M-CSF), antiapoptosis (survivin and Bcl-xL), angiogenesis (VEGF, bFGF, and HIF1α), metastasis (MMP2/9), and tumor evasion (IP-10 and RANTES) [19][20][21][22]. Overactivation of STAT3 has been associated with chronic inflammation, which drives the transformation of healthy to cancerous cells [23][24][25][26][27][28][29][30].…”

Section: Introductionmentioning

confidence: 99%

The IκB Kinase Inhibitor ACHP Targets the STAT3 Signaling Pathway in Human Non-Small Cell Lung Carcinoma Cells

et al. 2019

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STAT3 is an oncogenic transcription factor that regulates the expression of genes which are involved in malignant transformation. Aberrant activation of STAT3 has been observed in a wide range of human malignancies and its role in negative prognosis is well-documented.In this report, we performed high-throughput virtual screening in search of STAT3 signaling inhibitors using a cheminformatics platform and identified 2-Amino-6-[2-(Cyclopropylmethoxy)-6-Hydroxyphenyl]-4-Piperidin-4-yl Nicotinonitrile (ACHP) as the inhibitor of the STAT3 signaling pathway. The predicted hit was evaluated in non-small cell lung cancer (NSCLC) cell lines for its STAT3 inhibitory activity. In vitro experiments suggested that ACHP decreased the cell viability and inhibited the phosphorylation of STAT3 on Tyr705 of NSCLC cells. In addition, ACHP imparted inhibitory activity on the constitutive activation of upstream protein tyrosine kinases, including JAK1, JAK2, and Src. ACHP decreased the nuclear translocation of STAT3 and downregulated its DNA binding ability. Apoptosis was evidenced by cleavage of caspase-3 and PARP with the subsequent decline in antiapoptotic proteins, including Bcl-2, Bcl-xl, and survivin. Overall, we report that ACHP can act as a potent STAT3 signaling inhibitor in NSCLC cell lines.

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Capsazepine inhibits JAK/STAT3 signaling, tumor growth, and cell survival in prostate cancer

Cited by 110 publications

References 35 publications

Gallic acid has anticancer activity and enhances the anticancer effects of cisplatin in non‑small cell lung cancer A549 cells via the JAK/STAT3 signaling pathway

Gallic acid has anticancer activity and enhances the anticancer effects of cisplatin in non‑small cell lung cancer A549 cells via the JAK/STAT3 signaling pathway

IL-17 Activates the IL-6/STAT3 Signal Pathway in the Proliferation of Hepatitis B Virus-Related Hepatocellular Carcinoma

The IκB Kinase Inhibitor ACHP Targets the STAT3 Signaling Pathway in Human Non-Small Cell Lung Carcinoma Cells

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