Inhibition of the Wnt/β-catenin signaling pathway improves the anti-tumor effects of sorafenib against hepatocellular carcinoma

Lin, Hsiao-Hui; Feng, Wen‐Chi; Lu, Li-Chun; Shao, Yu‐Yun; Hsu, Chih‐Hung; Cheng, Ann‐Lii

doi:10.1016/j.canlet.2016.07.013

Cited by 44 publications

(36 citation statements)

References 33 publications

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“…In the present study, TF treatment inhibited the Wnt/β-catenin signaling pathway, which decreased the proliferation of A549 cells and increased apoptosis. A previous study demonstrated that the inhibition of the Wnt/β-catenin signaling pathway improves the anti-tumor effects of sorafenib in hepatocellular carcinoma (34). Another study demonstrated that downregulation of the Wnt/β-catenin signaling pathway inhibited the proliferation and increased apoptosis in A549 and H460 cells (35).…”

Section: Discussionmentioning

confidence: 98%

Total flavonoids suppress lung cancer growth via the COX‑2‑mediated Wnt/β‑catenin signaling pathway

Han

Fang

et al. 2020

Oncol Lett

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The aim of the present study was to explore the anti-cancer effects of total flavonoids (TF) on lung cancer and to investigate the underlying mechanism. The inhibitory effect of TF on the proliferation of A549 cells in vitro was measured using an MTT assay. The apoptotic rate of TF-treated A549 cells was analyzed using flow cytometry and terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling. Migration and invasion assays were performed to investigate the anti-migration effect of TF on A549 cells. Reverse-transcription quantitative PCR was used to analyze BCL2-like 2, BCL2, Bax, Bad, cyclooxygenase 2 (COX-2), Wnt and β-catenin mRNA expression levels in A549 cells. The in vivo anti-cancer effect of TF was investigated in a subcutaneous xenograft model of lung cancer in BALB/c nude mice. The results obtained in the present study revealed that TF exerted a significant inhibitory effect on the proliferation of A549 cells in a dose-dependent manner (P<0.01). TF induced apoptosis of A549 cells, which exhibited increased and decreased expression of pro-and anti-apoptotic genes, respectively. Furthermore, TF had a significant inhibitory effect on the migration and invasion of A549 cells (P<0.01). The mRNA expression levels of COX-2, Wnt and β-catenin were significantly downregulated in TF-treated A549 cells compared with controls. Additionally, treatment with TF inhibited tumor growth in mice, with a tumor inhibition rate of 64.07% compared with the controls. TF exhibited significant tumor inhibitory effects in vivo by promoting the apoptosis of tumor cells. In conclusion, the results suggested that TF may regulate lung cancer growth via the COX-2-Wnt/β-catenin signaling pathway. TF may serve as a novel anti-cancer agent for the treatment of lung cancer.

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Section: Discussionmentioning

confidence: 98%

Total flavonoids suppress lung cancer growth via the COX‑2‑mediated Wnt/β‑catenin signaling pathway

Han

Fang

et al. 2020

Oncol Lett

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“…Under this circumstance, rational combination with Wnt/b-catenin signaling inhibitors may improve the curative effects and reduce the side effects of platinum-based therapies. Recently, it has been reported that CBP plays essential roles in Wnt/b-catenin pathway-mediated chemoresistance via its association with b-catenin (16)(17)(18)(19)(20)(21)(22)(23)(24). Herein, we demonstrated that the inactivation of Wnt/CBP/b-catenin signaling via PRI-724 significantly enhanced the therapeutic efficacy of platinum therapy in RBMS3-deleted EOC, which further supports the notion that Wnt/b-catenin signaling is a druggable target for preventing chemoresistance and provides an attractive clinical strategy for treating RBMS3-deleted EOC.…”

Section: Discussionmentioning

confidence: 99%

“…The acetyltransferase CREB-binding protein (CBP) is essential for Wnt/b-catenin signaling-mediated chemoresistance via diverse mechanisms (16)(17)(18). Thus, a specific small-molecule inhibitor of the CBP/b-catenin interaction, ICG-001, was screened and tested, and appears to have distinctive antitumor effects in multiple cancer types via inactivation of the Wnt/CBP/b-catenin signaling (19)(20)(21)(22)(23)(24). In addition, the potential therapeutic value of PRI-724, which was derived from ICG-001 and is a secondgeneration CBP/b-catenin antagonist, is currently being tested in multiple clinical trials for the treatment of cancers, such as advanced colorectal and pancreatic cancers and myeloid malignancies (ClinicalTrials.gov ID: NCT02413853, NCT01764477, and NCT01606579).…”

Section: Introductionmentioning

confidence: 99%

Loss of RBMS3 Confers Platinum Resistance in Epithelial Ovarian Cancer via Activation of miR-126-5p/β-catenin/CBP signaling

Cao

Zhu

et al. 2019

Clinical Cancer Research

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Purpose: The development of resistance to platinumbased chemotherapy remains the unsurmountable obstacle in cancer treatment and consequently leads to tumor relapse. This study aims to investigate the mechanism by which loss of RBMS3 induced chemoresistance in epithelial ovarian cancer (EOC). Experimental Design: FISH and IHC were used to determine deletion frequency and expression of RBMS3 in 15 clinical EOC tissues and 150 clinicopathologically characterized EOC specimens. The effects of RBMS3 deletion and CBP/b-catenin antagonist PRI-724 in chemoresistance were examined by clone formation and Annexin V assays in vitro, and by intraperitoneal tumor model in vivo. The mechanism by which RBMS3 loss sustained activation of miR-126-5p/ b-catenin/CBP signaling and the effects of RBMS3 and miR-126-5p competitively regulating DKK3, AXIN1, BACH1, and NFAT5 was explored using CLIP-seq, RIP, electrophoretic mobility shift, and immunoblotting and immunofluorescence assays. Results: Loss of RBMS3 in EOC was correlated with the overall and relapse-free survival. Genetic ablation of RBMS3 significantly enhanced, whereas restoration of RBMS3 reduced, the chemoresistance ability of EOC cells both in vitro and in vivo. RBMS3 inhibited b-catenin/CBP signaling through directly associating with and stabilizing multiple negative regulators, including DKK3, AXIN1, BACH1, and NFAT5, via competitively preventing the miR-126-5p-mediated repression of these transcripts. Importantly, cotherapy of CBP/ b-catenin antagonist PRI-724 induced sensitization of RBMS3-deleted EOC to platinum therapy. Conclusions: Our results demonstrate that genetic ablation of RBMS3 contributes to chemoresistance and PRI-724 may serve as a potential tailored treatment for patients with RBMS3-deleted EOC.

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“…HBx could integrate into human genome and this transcript could activate Wnt signaling as a long noncoding RNA [84] . The associations between Wnt signaling and cancer initiation, tumor growth, metastasis, dormancy, immunity and tumor stem cell maintenance have been revealed, and Wnt signaling has exhibited numerous genetic abnormalities [85,86] as well as epigenetic alterations including modulation of DNA methylation. The overexpression of Wnt3a in cancerous tissues has been discovered, and its higher level was only found in sera of HCC patients from a cohort study in chronic liver diseases, although it is the first time to report as a novel specific marker for HCC diagnosis and prognosis.…”

Section: Perspectivesmentioning

confidence: 99%

Oncogenic Wnt3a: a promising specific biomarker in hepatocellular carcinoma

Yao¹,

Miao²,

Zheng³

et al. 2018

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Hepatocellular carcinoma (HCC) is still one of the most common and rapidly fatal malignancies worldwide with a multi-factorial, multi-step, complex process, and poor prognosis. Early discovery and effective therapy of HCC are of utmost importance. Recent studies demonstrated that Wnt/β-catenin pathway play important roles in occurrence and development of HCC including hepatocytes malignant transformation, metastasis, chemoresistance and liver cancer stem cells. Oncogenic wingless-type MMTV integration site family member 3a (Wnt3a) signaling is a promising biomarker in diagnosis and prognosis for HCC. This review presents current data on mechanisms of hepatocarcinogenesis involving participation of the Wnt canonical pathway, and focuses on the Wnt3a expression in HCC progression and its clinical application.

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Inhibition of the Wnt/β-catenin signaling pathway improves the anti-tumor effects of sorafenib against hepatocellular carcinoma

Cited by 44 publications

References 33 publications

Total flavonoids suppress lung cancer growth via the COX‑2‑mediated Wnt/β‑catenin signaling pathway

Total flavonoids suppress lung cancer growth via the COX‑2‑mediated Wnt/β‑catenin signaling pathway

Loss of RBMS3 Confers Platinum Resistance in Epithelial Ovarian Cancer via Activation of miR-126-5p/β-catenin/CBP signaling

Oncogenic Wnt3a: a promising specific biomarker in hepatocellular carcinoma

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