Convallatoxin promotes apoptosis and inhibits proliferation and angiogenesis through crosstalk between JAK2/STAT3 (T705) and mTOR/STAT3 (S727) signaling pathways in colorectal cancer

Zhang, Zhi Hong; Li, Ming Yue; Wang, Zhe; Zuo, Hong Xiang; Wang, Jing Ying; Xing, Yue; Jin, Changchun; Xu, G.; Li, Piao; Piao, Hulin; Ma, Juan; Jin, Xuejun

doi:10.1016/j.phymed.2020.153172

Cited by 74 publications

(40 citation statements)

References 31 publications

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“…Up to now, it could be concluded that genipin suppressed STAT-3 phosphorylation and nuclear translocation as well as inhibited its DNA-binding ability. STAT-3 dimers exported to the nucleus can activate the promoter of STAT-3 target genes and up-regulate the protein expression of these tumor-related genes, such as Survivin, Bcl-2, MMPs, SOCS3, and VEGF [ 18 ]. Western blot assay results further confirmed that genipin treatment decreased the expression of STAT-3 target genes in HCC cells (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Immunofluorescence staining was performed referred to previous studies [ 18 ]. Briefly, after fixation with 4% paraformaldehyde, cells were blocked and hybridized with the indicated primary antibodies for 12 h. Next, fluorescein isothiocyanate (FITC)-conjugated secondary antibodies were added and incubated for 2 h; 4′,6-diamidino-2-phenylindole (DAPI) was used for nuclear staining.…”

Section: Methodsmentioning

confidence: 99%

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RETRACTED ARTICLE: Genipin suppression of growth and metastasis in hepatocellular carcinoma through blocking activation of STAT-3

Hong

Lee

Clayton

et al. 2020

J Exp Clin Cancer Res

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Background: The signal transducer and activator of transcription-3 (STAT-3) can facilitate cancer progression and metastasis by being constitutively active via various signaling. Abundant evidence has indicated that STAT-3 may be a promising molecular target for cancer treatment. Methods: In this study, a dual-luciferase assay-based screening of 537 compounds for STAT-3 inhibitors of hepatocellular carcinoma (HCC) cells was conducted, leading to the identification of genipin. Effects of genipin on HCC were assessed in a patient-derived xenograft nude mice model. Western blotting assay, chromatin immunoprecipitation (ChIP) assay, molecular docking study, tube formation assay, three-dimensional top culture assay, histological examination, and immunofluorescence were utilized to evaluate the regulatory signaling pathway. Results: Our research demonstrated that genipin suppresses STAT-3 phosphorylation and nuclear translocation, which may be attributed to the binding capacity of this compound to the Src homology-2 (SH2) domain of STAT-3. In addition, the therapeutic effects of genipin in a patient-derived HCC xenograft nude mice model were also demonstrated. Conclusions: In conclusion, genipin showed therapeutic potential for HCC treatment by interacting with the SH2-STAT-3 domain and suppressing the activity of STAT-3. In the future, further research is planned to explore the potential role of genipin in combination with chemotherapy or radiotherapy for HCC.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

RETRACTED ARTICLE: Genipin suppression of growth and metastasis in hepatocellular carcinoma through blocking activation of STAT-3

Hong

Lee

Clayton

et al. 2020

J Exp Clin Cancer Res

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“…Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling pathway is believed as a crucial link implicated in invasion, survival, growth and angiogenesis of cancer cells [18]. Activated JAK could phosphorylate the tyrosine of STAT.…”

Section: Introductionmentioning

confidence: 99%

Oridonin inhibits tumor angiogenesis and induces vessel normalization in experimental colon cancer

Zhou¹,

Li²,

Shi³

et al. 2021

J. Cancer

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Purpose: Tumor blood vessels exhibit morphological and functional aberrancies. Its maturity and functionality are closely associated with colon cancer progression and therapeutic efficacy. The direct evidence proving whether oridonin (ORI) has vascular normalization promoting effect from which combination therapies will benefit is still lacking. Methods: We established a subcutaneous xenograft model of human colon cancer. The animals were divided into the Control and ORI-treated groups. Immunohistochemical analysis and TUNEL staining was applied to evaluate the proliferation, apoptosis and angiogenesis. Western blot analysis was employed to characterize the angiogenesis-related factors and JAK2/STAT3 signaling. Then, vascular normalization and macrophage reprogramming were assessed by immunofluorescence analysis. Results: The results showed that ORI obviously reduced tumor growth, diminished the numbers of Ki67 + cells and CD31 + microvessel density, while increased the numbers of TUNEL + cells. The expression levels of VEGF and bFGF proteins were dramatically down-regulated while the angiostatin and endostatin levels were increased in the ORI-treated group. Moreover, ORI therapy remarkably promoted the pericyte coverage of tumor vessels from days 5 to 10, with the highest pericyte coverage rate occurred at day 7. In the time window of vascular normalization, hypoxia of the tumor microenvironment was improved by ORI, the expression of HIF-1a was downregulated. Moreover, CD206 + macrophage cells were diminished in the ORI-treated group. These anticancer effects of ORI maybe partly mediated by suppressing JAK2/STAT3 signaling pathway. Conclusions: These results highlight the potential effect of ORI on anti-angiogenesis and inducing vessel normalization roles of ORI, and probably provide optimum time point for the ORI therapy in conjunction with the chemoradiotherapy or immunotherapy.

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“…Up to present, we could conclude that genipin suppressed STAT-3 phosphorylation and nuclear translocation as well as inhibited its DNAbinding ability. STAT-3 dimers exported to the nucleus can activate the promoter of STAT-3 target genes and up-regulates the protein expression of these tumor-related genes such as Survivin, Bcl-2, MMPs, SOCS3 and VEGF [17]. Western blot assay results further con rmed that genipin treatment decreased the expression of STAT-3 target genes in HCC cells (Fig 1e).…”

Section: Genipin Can Inhibit the Phosphorylation Of Stat-3 (Tyr) And mentioning

confidence: 70%

“…Immuno uorescence staining was performed refer to previous studies [17]. Brie y, after xation with 4% paraformaldehyde, cells were blocked and hybridizated with the indicated primary antibodies for 12 h. Next, uorescein isothiocyanate (FITC)-conjugated secondary antibodies were added and incubated for 2 h, 4′,6-diamidino-2-phenylindole (DAPI) was used for nuclear staining.…”

Section: Immuno Uorescent Stainingmentioning

confidence: 99%

Genipin Suppresses Growth and Metastasis in Hepatocellular Carcinoma Through Blocking Activation of STAT-3

Hong

Lee

Clayton

et al. 2020

Preprint

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Background Signal transducer and activator of transcription-3 (STAT-3) can facilitate cancer progression and metastasis by being constitutively active via various signalling. Abundant evidence has indicated that STAT-3 may be a promising molecular target for cancer treatment. Methods In this study, a dual-luciferase assay-based screening of 537 compounds for STAT-3 inhibitors of hepatocellular carcinoma (HCC) cells was conducted, leading to the identification of genipin. Effects of genipin on HCC were assessed in patient-derived xenograft mice model. Western blotting assay, chromatin immunoprecipitation (ChIP) assay, molecular docking study, tube formation assay, three-dimensional top culture assay, histological examination and immunofluorescence were utilized to evaluate the regulatory signalling pathway. Results Our research have demonstrated that genipin suppresses STAT-3 phosphorylation and nuclear translocation, which may attribute to the binding capacity of this compound to the Src homology-2 (SH2) domain of STAT-3. In addition, we also demonstrated the therapeutic effects of genipin in patient-derived HCC xenograft mice model.Conclusion In conclusion, genipin showed therapeutic potential for HCC treatment by interacting with SH2-STAT-3 domain and suppressing the activity of STAT-3. In future study, further research are expected for exploring the potential role of genipin in combination with chemotherapy or radiotherapy for HCC.

show abstract

Convallatoxin promotes apoptosis and inhibits proliferation and angiogenesis through crosstalk between JAK2/STAT3 (T705) and mTOR/STAT3 (S727) signaling pathways in colorectal cancer

Cited by 74 publications

References 31 publications

RETRACTED ARTICLE: Genipin suppression of growth and metastasis in hepatocellular carcinoma through blocking activation of STAT-3

RETRACTED ARTICLE: Genipin suppression of growth and metastasis in hepatocellular carcinoma through blocking activation of STAT-3

Oridonin inhibits tumor angiogenesis and induces vessel normalization in experimental colon cancer

Genipin Suppresses Growth and Metastasis in Hepatocellular Carcinoma Through Blocking Activation of STAT-3

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