Wogonin Induces Apoptosis and Reverses Sunitinib Resistance of Renal Cell Carcinoma Cells via Inhibiting CDK4-RB Pathway

Wang, Yong; Chen, Shouzhen; Sun, Song; Chen, Lipeng; Xia, Yangyang; Cui, Jianfeng; Wang, Wenfu; Jiang, Xuewen; Zhang, Lei; Zhu, Yao; Zou, Yongxin; Shi, Benkang

doi:10.3389/fphar.2020.01152

Cited by 25 publications

(19 citation statements)

References 54 publications

(65 reference statements)

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“…Forty-eight hours later, the viral supernatant was collected, and the BCa cells were infected for 48 h. Then, the infected cells were cultured in the medium containing 2 mg/L puromycin (Solarbio, P8230) for 3 d. Adenoviruses encoding the GFP or KDM6A were purchased from Vigenebio (Jinan, China). The siRNA transfections were performed as previously described [ 15 ]. The siRNAs targeting FOXA1 and ARHGDIB were synthesized by RiboBio (Guangzhou, China).…”

Section: Methodsmentioning

confidence: 99%

KDM6A-ARHGDIB axis blocks metastasis of bladder cancer by inhibiting Rac1

et al. 2021

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Background KDM6A, a histone demethylase, is frequently mutated in bladder cancer (BCa). However, the role and detailed molecular mechanism of KDM6A involved in bladder cancer progression remains unknown. Methods Tissue specimens were used to determine the expression levels and prognostic values of KDM6A and ARHGDIB. The MTT, colony formation, wound healing and Transwell migration and invasion assays were employed to detect the BCa cell proliferation, migration and invasion, respectively. Chemotaxis of macrophages was used to evaluate the ability of KDM6A to recruit macrophages. A subcutaneous tumour model and tail vein tumour injection in nude mice were used to assess the role of KDM6A in vivo. RNA sequencing, qPCR, Western blot, ChIP and phalloidin staining assay were performed to investigate the molecular functions of KDM6A. Dual-luciferase reporter assay was used to determine the effects of KDM6A and FOXA1 on the promoters of the ARHGDIB and KDM6A. Results We showed that the KDM6A inhibited the motility and invasiveness of the BCa cells. Mechanistically, KDM6A promotes the transcription of ARHGDIB by demethylating histone H3 lysine di/trimethylation (H3K27me2/3) and consequently leads to inhibition of Rac1. EZH2, which catalyses the methylation of H3K27, functions to silence ARHGDIB expression, and an EZH2 inhibitor can neutralize the metastatic effect caused by KDM6A deficiency. Furthermore, we demonstrated that FOXA1 directly binds to the KDM6A promoter and thus transactivates KDM6A, leading to diminished metastatic potential. Conclusion Our findings establish the critical role of the FOXA1-KDM6A-ARHGDIB axis in restraining the malignancy of BCa and identify KDM6A and EZH2 as potential therapeutic targets in the management of BCa.

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Section: Methodsmentioning

confidence: 99%

KDM6A-ARHGDIB axis blocks metastasis of bladder cancer by inhibiting Rac1

et al. 2021

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“…Cell proliferation and viability were measured by MTT, colony formation and EdU incorporation assays, which were performed as previously described 22 .…”

Section: Mtt Colony Formation and Edu Incorporation Assaysmentioning

confidence: 99%

“…Senescence-associated β-galactosidase (SA-β-gal) activity and tunel assay Senescence-associated β-galactosidase (SA-β-gal) activity was detected using the Senescence β-Galactosidase Staining Kit (#C0602, Beyotime Biotechnology, Jiangsu, China) and performed as previously described 22 .…”

Section: Wound-healing Transwell Migration and Invasion Assaysmentioning

confidence: 99%

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Berberine suppresses bladder cancer cell proliferation by inhibiting JAK1-STAT3 signaling via upregulation of miR-17-5p

Xia

Chen

Cui

et al. 2021

Biochemical Pharmacology

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Background: Berberine (BBR), an active component extracted from Coptis chinensis, has shown antitumor effects in multiple tumors. However, the underlying mechanisms haven't been fully elucidated. In this study, the effects of BBR on bladder cancer (BCa) cells and the underlying mechanisms were investigated both in vivo and vitro. Methods: MTT, colony formation, EdU incorporation assays and xenograft tumor models were performed to evaluate the anti-proliferation effects of BBR on BCa cells in vivo and vitro. The roles of BRR in migration and invasion of BCa cells were investigated by wound-healing, transwell migration and invasion assays. The apoptosis and senescence induced by BBR were determined by ow cytometry, tunel assay and senescence-associated β-galactosidase (SA-β-gal) activity assay. Potential candidate targets were screened using western blot. The relationships between miR-17-5p and JAK1-STAT3 pathway were then predicted using in-silico analysis and identi ed by dual-luciferase reporter assay. The regulatory mechanism of miR-17-5p mediated suppression of JAK1-STAT3 pathway caused by BBR treatment was validated by qRT-PCR and western blot.Results: We found that BBR showed signi cant cytotoxic effects against bladder cancer (BCa) cell lines both in vivo and vitro, with much lower cytotoxic effects on human normal urothelial cell line SV-HUC-1. BBR treatment induced DNA replication defects and cycle cell arrest, resulting in apoptosis or cell senescence, depending on p53 status, in BCa cells. Mechanically, BBR exerted anti-tumor effects on BCa cells through inhibiting JAK1-STAT3 signaling via promoting expression of miR-17-5p, which directly bound to 3' UTR of JAK1 and STAT3 and downregulated their expressions. Conclusion:Our results demonstrate that BBR exerts anti-tumor effects through perturbing JAK1-STAT3 signaling via upregulating expression of miR-17-5p in BCa cells, and BBR may serve as a potential therapeutic option for BCa treatment.

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“…Berberine chloride and stattic were dissolved in Dimethyl sulfoxide (DMSO), and MTT was dissolved in phosphate-buffered solution (PBS). Primary antibodies for western blot were presented in Supplementary Table 1. MTT, colony formation, and EdU incorporation assays Cell proliferation and viability were measured by MTT, colony formation and EdU incorporation assays, which were performed as previously described 22 .…”

Section: Reagents and Antibodiesmentioning

confidence: 99%

Berberine Suppresses Bladder Cancer Cell Proliferation by Inhibiting JAK1-STAT3 Signaling via Upregulation of miR-17-5p

Xia

Chen

Cui

et al. 2020

Preprint

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Background: Berberine (BBR), an active component extracted from Coptis chinensis, has shown anti-tumor effects in multiple tumors. However, the underlying mechanisms haven’t been fully elucidated. In this study, the effects of BBR on bladder cancer (BCa) cells and the underlying mechanisms were investigated both in vivo and vitro. Methods: MTT, colony formation, EdU incorporation assays and xenograft tumor models were performed to evaluate the anti-proliferation effects of BBR on BCa cells in vivo and vitro. The roles of BRR in migration and invasion of BCa cells were investigated by wound-healing, transwell migration and invasion assays. The apoptosis and senescence induced by BBR were determined by flow cytometry, tunel assay and senescence-associated β-galactosidase (SA-β-gal) activity assay. Potential candidate targets were screened using western blot. The relationships between miR-17-5p and JAK1-STAT3 pathway were then predicted using in-silico analysis and identified by dual-luciferase reporter assay. The regulatory mechanism of miR-17-5p mediated suppression of JAK1-STAT3 pathway caused by BBR treatment was validated by qRT-PCR and western blot.Results: We found that BBR showed significant cytotoxic effects against bladder cancer (BCa) cell lines both in vivo and vitro, with much lower cytotoxic effects on human normal urothelial cell line SV-HUC-1. BBR treatment induced DNA replication defects and cycle cell arrest, resulting in apoptosis or cell senescence, depending on p53 status, in BCa cells. Mechanically, BBR exerted anti-tumor effects on BCa cells through inhibiting JAK1-STAT3 signaling via promoting expression of miR-17-5p, which directly bound to 3’ UTR of JAK1 and STAT3 and downregulated their expressions. Conclusion: Our results demonstrate that BBR exerts anti-tumor effects through perturbing JAK1-STAT3 signaling via upregulating expression of miR-17-5p in BCa cells, and BBR may serve as a potential therapeutic option for BCa treatment.

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Wogonin Induces Apoptosis and Reverses Sunitinib Resistance of Renal Cell Carcinoma Cells via Inhibiting CDK4-RB Pathway

Cited by 25 publications

References 54 publications

KDM6A-ARHGDIB axis blocks metastasis of bladder cancer by inhibiting Rac1

KDM6A-ARHGDIB axis blocks metastasis of bladder cancer by inhibiting Rac1

Berberine suppresses bladder cancer cell proliferation by inhibiting JAK1-STAT3 signaling via upregulation of miR-17-5p

Berberine Suppresses Bladder Cancer Cell Proliferation by Inhibiting JAK1-STAT3 Signaling via Upregulation of miR-17-5p

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