Fucoidan inhibits EGFR redistribution and potentiates sorafenib to overcome sorafenib-resistant hepatocellular carcinoma

Luo, Jialiang; Li, Lei; Zhu, Zhengyumeng; Chang, Bo Yoon; Deng, Fan; Wang, Di; Xiao, Lü; Zuo, Daming; Chen, Qing‐Yun; Zhou, Jia

doi:10.1016/j.biopha.2022.113602

Cited by 15 publications

(11 citation statements)

References 46 publications

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“…Sorafenib is considered as a standard first‐line agent for advanced liver cancer [50]; however, the insensitivity of some patients to sorafenib limits its efficacy [11]. Therefore, increasing the sensitivity to sorafenib is crucial for the treatment of liver cancer.…”

Section: Discussionmentioning

confidence: 99%

“…Epidermal growth factor receptor (EGFR), a member of the surface receptor tyrosine kinase family, contributes to tumor angiogenesis and metastasis [10]. More than 50% of patients with liver cancer demonstrate EGFR overexpression [11]. Wild‐type EGFR can activate multiple signal transduction pathways, including the mitogen‐activated protein kinase (MAPK) and janus kinase (JAK)‐signal transducers and activators of transcription (STAT) signaling pathways [12].…”

Section: Introductionmentioning

confidence: 99%

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SERPINE2 promotes liver cancer metastasis by inhibiting c‐Cbl‐mediated EGFR ubiquitination and degradation

Zhang,

Jia,

Dai

et al. 2024

Cancer Communications

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BackgroundLiver cancer is a malignancy with high morbidity and mortality rates. Serpin family E member 2 (SERPINE2) has been reported to play a key role in the metastasis of many tumors. In this study, we aimed to investigate the potential mechanism of SERPINE2 in liver cancer metastasis.MethodsThe Cancer Genome Atlas database (TCGA), including DNA methylation and transcriptome sequencing data, was utilized to identify the crucial oncogene associated with DNA methylation and cancer progression in liver cancer. Data from the TCGA and RNA sequencing for 94 pairs of liver cancer tissues were used to explore the correlation between SERPINE2 expression and clinical parameters of patients. DNA methylation sequencing was used to detect the DNA methylation levels in liver cancer tissues and cells. RNA sequencing, cytokine assays, immunoprecipitation (IP) and mass spectrometry (MS) assays, protein stability assays, and ubiquitination assays were performed to explore the regulatory mechanism of SERPINE2 in liver cancer metastasis. Patient‐derived xenografts and tumor organoid models were established to determine the role of SERPINE2 in the treatment of liver cancer using sorafenib.ResultsBased on the public database screening, SERPINE2 was identified as a tumor promoter regulated by DNA methylation. SERPINE2 expression was significantly higher in liver cancer tissues and was associated with the dismal prognosis in patients with liver cancer. SERPINE2 promoted liver cancer metastasis by enhancing cell pseudopodia formation, cell adhesion, cancer‐associated fibroblast activation, extracellular matrix remodeling, and angiogenesis. IP/MS assays confirmed that SERPINE2 activated epidermal growth factor receptor (EGFR) and its downstream signaling pathways by interacting with EGFR. Mechanistically, SERPINE2 inhibited EGFR ubiquitination and maintained its protein stability by competing with the E3 ubiquitin ligase, c‐Cbl. Additionally, EGFR was activated in liver cancer cells after sorafenib treatment, and SERPINE2 knockdown‐induced EGFR downregulation significantly enhanced the therapeutic efficacy of sorafenib against liver cancer. Furthermore, we found that SERPINE2 knockdown also had a sensitizing effect on lenvatinib treatment.ConclusionsSERPINE2 promoted liver cancer metastasis by preventing EGFR degradation via c‐Cbl‐mediated ubiquitination, suggesting that inhibition of the SERPINE2‐EGFR axis may be a potential target for liver cancer treatment.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

SERPINE2 promotes liver cancer metastasis by inhibiting c‐Cbl‐mediated EGFR ubiquitination and degradation

Zhang,

Jia,

Dai

et al. 2024

Cancer Communications

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“…Fucoidan has been investigated before in combination with Avastin but for the treatment of exudative age-related macular degeneration, results showed an in vitro reduction in the expression of VEGF (Dithmer et al, 2014). While the combination of fucoidan with sorafenib has been recently reported in vitro in a sorafenib resistant cell line (HepG2-SR) and in vivo using tumour xenograft in nude mice (Luo et al, 2022). The results of this study focused on the epidermal growth factor receptor (EGFR) pathway and showed that fucoidan could help overcome sorafenib resistance in HCC via binding to EGFR (Luo et al, 2022).…”

Section: Discussionmentioning

confidence: 99%

“…While the combination of fucoidan with sorafenib has been recently reported in vitro in a sorafenib resistant cell line (HepG2-SR) and in vivo using tumour xenograft in nude mice (Luo et al, 2022). The results of this study focused on the epidermal growth factor receptor (EGFR) pathway and showed that fucoidan could help overcome sorafenib resistance in HCC via binding to EGFR (Luo et al, 2022). Nonetheless, despite these previously reported promising findings, our research explores a poorly investigated area of research which is the interaction between fucoidan and the key angiogenic pathway especially in combination with sorafenib and Avastin in HCC.…”

Section: Discussionmentioning

confidence: 99%

Antiangiogenic drugs in combination with seaweed fucoidan: A mechanistic in vitro and in vivo study exploring the VEGF receptor and its downstream signaling molecules in hepatic cancer

et al. 2023

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Hepatocellular carcinoma (HCC) is one of the most common cancers reported worldwide with poor morbidity and high mortality rates. HCC is a very vascular solid tumour as angiogenesis is not only a key driver for tumour progression but also an exciting therapeutic target. Our research investigated the use of fucoidan, a sulfated polysaccharide readily abundant in edible seaweeds commonly consumed in Asian diet due to their extensive health benefits. Fucoidan was reported to possess a strong anti-cancer activity, but its anti-angiogenic potential is still to be fully unraveled. Our research investigated fucoidan in combination with sorafenib (an anti-VEGFR tyrosine kinase inhibitor) and Avastin® (bevacizumab, an anti-VEGF monoclonal antibody) in HCC both in vitro and in vivo. In vitro on HUH-7 cells, fucoidan had a potent synergistic effect when combined with the anti-angiogenic drugs and significantly reduced HUH-7 cell viability in a dose dependent manner. Using the scratch wound assay to test cancer cell motility, sorafenib, A + F (Avastin and fucoidan) or S + F (sorafenib and fucoidan) treated cells consistently showed an unhealed wound and a significantly smaller %wound closure (50%–70%) versus untreated control (91%–100%) (p < 0.05, one-way ANOVA). Using RT-qPCR; fucoidan, sorafenib, A + F and S + F significantly reduced the expression of the pro-angiogenic PI3K/AKT/mTOR and KRAS/BRAF/MAPK pathways by up to 3 folds (p < 0.05, one-way ANOVA versus untreated control). While ELISA results revealed that in fucoidan, sorafenib, A + F and S + F treated cells, the protein levels of caspases 3, 8, and 9 was significantly increased especially in the S + F group showing 40- and 16-times higher caspase 3 and 8 protein levels, respectively (p < 0.05, one-way-ANOVA versus untreated control). Finally, in a DEN-HCC rat model, H&E staining revealed larger sections of apoptosis and necrosis in the tumour nodules of rats treated with the combination therapies and immunohistochemical analysis of the apoptotic marker caspase 3, the proliferation marker Ki67 and the marker for angiogenesis CD34 showed significant improvements when the combination therapies were used. Despite the promising findings reported herein that highlighted a promising chemomodulatory effect of fucoidan when combined with sorafenib and Avastin, further investigations are required to elucidate potential beneficial or adversary interactions between the tested agents.

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“…HK-2 cells (2 × 10 3 cells per well) were seeded into 96-well plates. After overnight incubation, cells were treated with indicated stimulation for 24 or 48 h, and CCK-8 solution was added for 4 h [ 19 ]. Cell viability was determined by detection at an absorbance wavelength at 450 nm.…”

Section: Methodsmentioning

confidence: 99%

FUT1-mediated terminal fucosylation acts as a new target to attenuate renal fibrosis

Luo

Mao

Zhu

et al. 2023

Mol Med

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Backgrounds Renal fibrosis is a common pathologic process of most chronic kidney diseases (CKDs), becoming one of the major public health problems worldwide. Terminal fucosylation plays an important role in physiological homeostasis and pathological development. The present study aimed to explore the role of terminal fucosylation during kidney fibrogenesis and propose a possible anti-fibrosis treatment via suppressing aberrant terminal fucosylation. Methods We investigated the expression level of fucosyltransferase1 (FUT1) in CKD patients by using public database. Then, we further confirmed the level of terminal fucosylation by UEA-I staining and FUT1 expression in unilateral ureteral obstruction (UUO)-induced renal fibrosis mice. Immunostaining, qPCR, western blotting and wound healing assay were applied to reveal the effect of FUT1 overexpression in human kidney proximal tubular epithelial cell (HK-2). What’s more, we applied terminal fucosylation inhibitor, 2-Deoxy-D-galactose (2-D-gal), to determine whether suppressing terminal fucosylation ameliorates renal fibrosis progression in vitro and in vivo. Results Here, we found that the expression of FUT1 significantly increased during renal fibrosis. In vitro experiments showed upregulation of epithelial-mesenchymal transition (EMT) after over-expression of FUT1 in HK-2. Furthermore, in vivo and in vitro experiments indicated that suppression of terminal fucosylation, especially on TGF-βR I and II, could alleviate fibrogenesis via inhibiting transforming growth factor-β (TGF-β)/Smad signaling. Conclusions The development of kidney fibrosis is attributed to FUT1-mediated terminal fucosylation, shedding light on the inhibition of terminal fucosylation as a potential therapeutic treatment against renal fibrosis.

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Fucoidan inhibits EGFR redistribution and potentiates sorafenib to overcome sorafenib-resistant hepatocellular carcinoma

Cited by 15 publications

References 46 publications

SERPINE2 promotes liver cancer metastasis by inhibiting c‐Cbl‐mediated EGFR ubiquitination and degradation

SERPINE2 promotes liver cancer metastasis by inhibiting c‐Cbl‐mediated EGFR ubiquitination and degradation

Antiangiogenic drugs in combination with seaweed fucoidan: A mechanistic in vitro and in vivo study exploring the VEGF receptor and its downstream signaling molecules in hepatic cancer

FUT1-mediated terminal fucosylation acts as a new target to attenuate renal fibrosis

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