Research ArticleExperimental Studies
Open Access

Fucoidan Treatment Leads to Attenuated Growth Factor Signaling and Reduced Proliferation in Neuroblastoma Cells

NIKLAS WEBER, NINA SOPHIE POMMERT, MEIKE KAEHLER, INGOLF CASCORBI, SUSANNE ALBAN and VICKI WAETZIG
Anticancer Research July 2025, 45 (7) 2749-2762; DOI: https://doi.org/10.21873/anticanres.17644

Abstract

Background/Aim: Brown algae-derived sulfated polysaccharides, termed as fucoidans, are pharmacologically active substances with pleiotropic anticancer properties, but without known toxicity. In neuroblastoma, an aggressive malignancy with a heterogeneous biological basis, multimodal therapeutic approaches are mandatory for high-risk patients, but these are associated with a problematic safety profile. The present study aimed to examine fucoidan-mediated effects in human neuroblastoma cells to assess their putative tumor-suppressive potential.

Materials and Methods: In Kelly or SH-SY5Y cells, viability was quantified using cell fitness assays. Expression was analyzed using quantitative PCR and the regulation or phosphorylation of proteins using enzyme-linked immunoabsorbent assays (ELISA) or Western blots.

Results: In Kelly and SH-SY5Y cells, treatment with fucoidans from Fucus vesiculosus (F.v.) or Saccharina latissima (S.l.) for 3 days did not induce cell death, but significantly reduced proliferation (p<0.001), which was associated with attenuated signaling of hepatocyte growth factor (HGF), insulin-like growth factor 2 (IGF2) and vascular endothelial growth factor (VEGF). Despite cell type- and fucoidan-specific differences, co-administration of the fucoidans from F.v. or S.l. and specific receptor inhibitors of HGF (tepotinib), IGF2 (linsitinib) or VEGF (cediranib), distinctly reduced cell viability compared to inhibitor treatment alone in both cell lines (p<0.001). Interestingly, the fucoidan from S.l. also enhanced the antitumor effect of the endothelial growth factor (EGF) receptor inhibitor erlotinib in Kelly and SH-SY5Y cells, although endogenous EGF was not detectable.

Conclusion: Fucoidan treatment decreased proliferation in neuroblastoma cells by interfering with the signal transduction of HGF, IGF2, and VEGF, which substantially increased cellular susceptibility to specific growth factor receptor inhibitors.

Keywords:

Introduction

Neuroblastoma is the most prevalent extracranial solid tumor in children and accounts for approximately 15% of pediatric cancer-related fatalities (1, 2). Tumorigenesis in the adrenal medulla or sympathetic ganglia is initiated by deregulation of differentiation and death of sympathoadrenal neural crest cells during embryogenesis, which can lead to metastasis in advanced stages (1, 2). Among other mediators, growth factors have an important role in tumor development and progression by promoting continuous proliferation and thereby facilitating the formation of malignant cells (3). Especially insulin-like growth factor 2 (IGF2) and one of its receptors, IGF1R, are widely expressed in neuroblastoma specimens (4, 5) to sustain survival and attenuate apoptosis (3). Enhanced cell growth can also be mediated by endothelial growth factor (EGF) in neuroblastoma cells (6), while hepatocyte growth factor (HGF) signaling is often associated with invasiveness and malignant progression (7). Vascular endothelial growth factor (VEGF) is particularly important for angiogenesis, but can also activate survival pathways (8-10).

Brown algae are a rich source of biologically active compounds, e.g. polyphenols like phlorotannins (11), carotenoids like fucoxanthin (12, 13), or fucose-containing sulfated polysaccharides, termed as fucoidans (14). Especially the latter have attracted much attention for their anticancer activities, which include cytotoxic effects on cancer cells or inhibition of tumor growth by interfering with cell cycle progression (15, 16). Fucoidans have been reported to enhance diverse anticancer approaches in various cancer cells (17, 18). Interestingly, physiological processes like proliferation or differentiation of non-malignant cells are not attenuated, but rather facilitated (19-21). Fucoidans can also impair VEGF signaling and thereby reduce tumor angiogenesis (22). It was even observed that mediators of tissue invasion and metastasis like transforming growth factor beta (TGF beta) are affected by the application of fucoidan (14, 23). However, the findings on fucoidan treatment in neuroblastoma cells are inconsistent, ranging from ineffectiveness (24) to protection in proinflammatory or oxidative stress conditions (25, 26). Furthermore, all previous studies in neuroblastoma cells used fucoidans from different algae, which might contribute to the heterogeneous results due to large variations of their structural composition depending on algae species, harvest time and place, numerous environmental factors as well as the isolation procedure (27, 28).

Therefore, the aim of the present study was to examine the effects of two fucoidans, which have been well-characterized and compared in the same experimental settings (29-33), in SH-SY5Y and Kelly human neuroblastoma cells. Interestingly, despite cell type-specific differences, the extracts from Fucus vesiculosus or Saccharina latissima reduced proliferation via attenuation of growth factor signaling without inducing cell death.

Materials and Methods

Cell culture. Human Kelly and SH-SY5Y neuroblastoma cells were cultured and stimulated as described previously (34, 35). In the present study, the cells were incubated with the following substances: cediranib (1 μM, Absource Diagnostics, Munich, Germany), EGF (100 ng/ml, Thermo Fisher Scientific, Dreieich, Germany), erlotinib (10 μM, Absource Diagnostics), fucoidan from Fucus vesiculosus (5 μg/ml, 10 μg/ml or 50 μg/ml, Sigma-Aldrich, Taufkirchen, Germany), HGF (100 ng/ml, Thermo Fisher Scientific), IGF2 (100 ng/ml, Thermo Fisher Scientific), linsitinib (1 μM, Absource Diagnostics), tepotinib (5 μM, Absource Diagnostics) or VEGF-165 (100 ng/ml, Thermo Fisher Scientific). The extraction, purification, structural characterization and basic activities of the fucoidan from Saccharina latissima have been previously described (36).

Determining cell viability, proliferation and cytotoxicity in Kelly and SH-SY5Y cells. All experiments were performed as described previously (34, 35).

Western blots. Whole cell lysates and western blots were performed as described previously (34, 35). In this study, antibodies against the following targets were used: Akt (sc-5298, AB_626658, 1:1,000, Santa Cruz Biotechnology, Heidelberg, Germany), ERK1/2 (sc-514302, AB_2571739, 1:1,000, Santa Cruz Biotechnology), JNK (sc-7345, AB_675864, 1:1,000, Santa Cruz Biotechnology), phospho-Akt (4060, AB_2315049, 1:1,000, Cell Signalling Technology, Frankfurt, Germany), phospho-ERK1/2 (9101, AB_331646, 1:1,000 Cell Signalling Technology), phospho-JNK (9251, AB_331659, 1:1,000, Promega, Mannheim, Germany).

ELISAs. ELISAs for HGF, IGF2 and VEGF levels in cell culture supernatants were performed as described previously (34, 35).

RNA extraction and quantitative PCR. All procedures were performed as described previously (34, 35). In the present study, qRT-PCRs of HGF (Hs00300159_m1), IGF2 (Hs00171254_m1) and VEGF (Hs00900055_m1) mRNA were performed in triplicates using beta actin (Hs1060665) as an internal control. Data were analyzed using the ΔΔCt-method as previously described (37).

Statistical analyses. All analyses were performed as described previously (34, 35).

Results

Fucoidan-mediated viability and proliferation of SH-SY5Y cells. First, it was examined if the fucoidans from Fucus vesiculosus (F.v.) and Saccharina latissima (S.l.) affected ATP levels of SH-SY5Y cells as an index of cell viability. After an incubation with 5, 10 or 50 μg/ml of the fucoidan from F.v. for 72 h, only stimulation with 50 μg/ml reduced the ATP levels in SH-SY5Y cells by 18% (p<0.01), while lower concentrations did not affect ATP levels (Figure 1A). In contrast, treatment with 5, 10 or 50 μg/ml of the S.l. fucoidan decreased ATP levels by 21%, 25% or 27% (p< 0.001), respectively (Figure 1A). For the following experiments, both fucoidans were used in a concentration of 50 μg/ml.

Figure 1.
Figure 1.

ATP levels, proliferation and cytotoxicity after treatment of SH-SY5Y cells with fucoidans for 72 h. (A) ATP levels were determined after treatment with fucoidan F.v. (5, 10 or 50 μg/ml) or S.l. (5, 10 or 50 μg/ml) (n=6). (B) BrdU incorporation or cytotoxicity were measured after incubation with F.v. (50 μg/ml) or S.l. fucoidan (50 μg/ml) (n=6). (C, D) The activation of Akt, ERK1/2 or JNK was determined after application of fucoidan from (C) F.v. (50 μg/ml) or (D) S.l. (50 μg/ml) using antibodies against the phosphorylated forms of the kinases using western blots (n=4). ***p<0.001, **p<0.01, *p<0.05 for control vs. fucoidan-treated cells. C: control, n.s.: non-significant.

Next, it was examined if the fucoidans reduced cellular levels of ATP by attenuating proliferation or by inducing cell death. When SH-SY5Y cells were treated with fucoidans from F.v. or S.l. for 72 h, proliferation was reduced by 24% (p<0.01) or 44% (p<0.001), while no cytotoxic reactions were observed (Figure 1B). Furthermore, signaling pathways important for cellular survival were examined. Application of the F.v. fucoidan did not alter the phosphorylation patterns of Akt, ERK1/2 or JNK (Figure 1C), whereas the S.l. fucoidan significantly decreased the activity of Akt by 21% (p<0.05) and ERK1/2 by 42% (p<0.01). The phosphorylation of JNK was not affected (Figure 1D).

Thus, both fucoidans reduced the proliferation of SH-SY5Y cells, but did not induce cell death.

Fucoidan-modulated growth factor signaling in SH-SY5Y cells. In the next set of experiments, it was analyzed if the decreased proliferation of SH-SY5Y cells in response to both fucoidans resulted from altered growth factor signaling, as previously observed for several fucoidans (38-40).

First, it was examined if the fucoidans from F.v. or S.l. affected the expression or the release of EGF, HGF, IGF2 or VEGF in SH-SY5Y cells. When mRNA levels were analyzed using qRT-PCR, the expression of EGF remained below the detection limit (data not shown). However, treatment with 50 μg/ml fucoidan from F.v. for 72 h attenuated the expression of HGF, IGF2 or VEGF by 20%, 19% or 22% (p< 0.05), respectively (Figure 2A). Incubation with 50 μg/ml S.l. fucoidan reduced the mRNA levels of HGF, IGF2 or VEGF by 58%, 74% or 38% (p<0.001), respectively.

Figure 2.
Figure 2.

Fucoidan-mediated effects on growth factor signaling in SH-SY5Y cells after 72 h of treatment. (A) The expression of HGF, IGF2 or VEGF was analyzed using RT-qPCR in response to fucoidans from F.v. (50 μg/ml) or S.l. (50 μg/ml) (n=4). (B) The amount of HGF, IGF2 or VEGF in cell culture supernatants was analyzed using ELISA in response to treatment with fucoidans from F.v. (50 μg/ml) or S.l. (50 μg/ml) (n=4). The growth factors (C) EGF (100 ng/ml), (D) HGF (100 ng/ml), (E) IGF2 (100 ng/ml) or (F) VEGF (100 ng/ml) were applied to SH-SY5Y cells for 72 h alone or in combination with fucoidans from F.v. (50 μg/ml) or S.l. (50 μg/ml), before ATP levels were determined (n=5). Control=100; ***p<0.001, **p<0.01, *p<0.05 for control vs. cells treated with fucoidans from F.v. or S.l., one of the growth factors or a combination of both; ###p<0.001, ##p<0.01, #p<0.05 for growth factor-stimulated cells vs. cells, which were simultaneously incubated with one of the growth factors and one of the fucoidans.

The amount of the growth factors in cell culture supernatants was quantified by performing ELISA. Application of 50 μg/ml F.v. fucoidan reduced the release of HGF, IGF2 or VEGF by 21% (p<0.05), 26% or 28% (p< 0.01), respectively. Incubation with 50 μg/ml S.l. fucoidan also decreased the protein levels of HGF (by 82%, p<0.001), IGF2 (by 77%, p<0.001) or VEGF (by 31%, p<0.01) compared to control cells (Figure 2B).

It was also analyzed if the fucoidans still reduced ATP levels, when the growth factors EGF, HGF, IGF2 or VEGF were supplemented to the growth medium. For this, the cells were either incubated with 100 ng/ml of each growth factor alone or in combination with the fucoidans from F.v. (50 μg/ml) or S.l. (50 μg/ml) for 72 h, before ATP levels were determined. After application of EGF (100 ng/ml), the ATP levels increased by 56% (p<0.001; Figure 2C) compared to control cells. When SH-SY5Y cells were concomitantly treated with 50 μg/ml F.v. fucoidan, ATP levels were still substantially elevated (by 30%, p<0.001 vs. controls). The simultaneous incubation with EGF (100 ng/ml) and 50 μg/ml S.l. fucoidan enhanced ATP levels by 21%, which was higher compared to control cells (p<0.05), but lower compared to EGF-supplemented cells (p<0.05) (Figure 2C).

Treatment with HGF (100 ng/ml) did not change ATP levels, while co-application of 50 μg/ml F.v. fucoidan reduced ATP levels by 16% (p<0.05) compared to control cells. Concomitant incubation with HGF (100 ng/ml) and 50 μg/ml fucoidan from S.l. further decreased ATP levels by 33% compared to control as well as HGF-treated cells (p< 0.001) (Figure 2D).

In response to IGF2 (100 ng/ml), ATP levels of SH-SY5Y cells were increased by 36% (p<0.001). When the cells were simultaneously incubated with 50 μg/ml F.v. fucoidan, ATP levels were reduced by 13% (p<0.05 vs. controls; p<0.001 vs. IGF2-treated cells). Co-application of IGF2 (100 ng/ml) and 50 μg/ml of the fucoidan from S.l. decreased ATP levels by 27% (p<0.001) (Figure 2E).

After treatment with VEGF (100 ng/ml), ATP levels were increased by 25% (p<0.001) compared to control cells. Simultaneous incubation with VEGF (100 ng/ml) and 50 μg/ml F.v. fucoidan reduced ATP levels by 11%, which were significantly lower compared to VEGF-treated cells (p< 0.001). When VEGF (100 ng/ml) and 50 μg/ml fucoidan from S.l. were concomitantly applied to the cells, ATP levels decreased by 21% (p<0.001 vs. controls) (Figure 2F).

Summing up, despite growth factor-specific differences, the effects of EGF, HGF, IGF2 and VEGF on ATP levels were attenuated by co-incubation with both fucoidans.

Next, it was assessed whether the fucoidan-mediated reduction of growth factor release influenced the effects of specific growth factor receptor inhibitors on ATP levels. Accordingly, SH-SY5Y cells were incubated with receptor inhibitors alone or in combination with one of the fucoidans for 48 h, before ATP levels were measured. The following substances were chosen: erlotinib (EGFR), tepotinib (c-Met), linsitinib (IGF1R) and cediranib (VEGFR2). After application of erlotinib (10 μM), ATP levels were reduced by 22% (p< 0.001 vs. controls). When the cells were simultaneously treated with 50 μg/ml fucoidans from F.v. or S.l., ATP levels were decreased by 36% or 41%, respectively (p<0.001 vs. controls), which was also significantly lower than those observed in erlotinib-treated cells (p<0.001) (Figure 3A). Incubation with tepotinib (5 μM) did not change ATP levels, while co-treatment with 50 μg/ml of the fucoidans from F.v. or S.l. reduced ATP levels by 52% or 55%, respectively (p< 0.001 vs. controls or tepotinib-treated cells) (Figure 3B). In response to linsitinib (1 μM), ATP levels of SH-SY5Y cells were attenuated by 32% (p<0.001) compared to control cells. When 50 μg/ml of the fucoidans from F.v. or S.l. were added, ATP levels were reduced by 64% or 70%, respectively (p<0.001 vs. controls), which was also distinctly lower than those in linsitinib-treated cells (p<0.001) (Figure 3C). After stimulation with cediranib (1 μM), ATP levels were decreased by 14% (p<0.05) compared to control cells. Co-treatment with 50 μg/ml F.v. fucoidan reduced ATP levels by 47% (p<0.001 vs. controls and cediranib-treated cells). When cediranib and 50 μg/ml of S.l. fucoidan were concomitantly applied, ATP levels were decreased by 49% (p< 0.001 vs. controls or cediranib-treated cells) (Figure 3D). Thus, both fucoidans not only reduced the endogenous levels of HGF, IGF2 or VEGF in SH-SY5Y cells and interfered with growth factor-induced levels of ATP, but also enhanced the effects of specific growth factor receptor inhibitors.

Figure 3.
Figure 3.

Fucoidan-mediated effects on growth factor receptor inhibition in SH-SY5Y cells. (A-D) The growth factor receptor inhibitors (A) erlotinib (10 μM), (B) tepotinib (5 μM), (C) linsitinib (1 μM) or (D) cediranib (1 μM) were applied to SH-SY5Y cells for 48 h alone (Ø) or in combination with fucoidans from F.v. (50 μg/ml) or S.l. (50 μg/ml), before ATP levels were determined (n=5). ***p<0.001, *p<0.05 for control vs. fucoidan-treated cells; ###p<0.001, for inhibitor-treated cells vs. cells, which were simultaneously incubated with one of the growth factor receptor inhibitors and one of the fucoidans.

Fucoidan-modulated growth factor signaling in Kelly cells. As fucoidan-mediated effects were often observed to be cell type-specific, it was also examined whether Kelly cells, a human MYCN-amplified neuroblastoma cell line, were also affected by treatment with both fucoidans. First, viability, proliferation and cytotoxicity were analyzed. Again, both fucoidans were used in a concentration of 50 μg/ml. After incubating Kelly cells with the fucoidans for 72 h, the different cellular parameters were determined. Treatment with 50 μg/ml of the fucoidan from F.v. reduced the ATP levels of Kelly cells by 22%, BrdU incorporation by 19% and cytotoxicity by 16% (p<0.001) compared to control cells. Application of S.l. fucoidan decreased ATP levels by 34% (p<0.001 vs. controls), proliferation by 47% (p< 0.001 vs. controls) and cytotoxicity by 15% (p<0.01 vs. controls) (Figure 4A).

Figure 4.
Figure 4.

ATP levels and growth factor-mediated effects after treatment with fucoidans in Kelly cells. (A) Effect of fucoidans from F.v. (50 μg/ml) or S.l. (50 μg/ml) on ATP levels, proliferation (BrdU incorporation) and cytotoxicity in Kelly after 72 h of treatment normalized to control cells (n=5). (B) After application of the fucoidans from F.v. (50 μg/ml) or S.l. (50 μg/ml) for 72 h, the amount of HGF, IGF2 or VEGF in Kelly cell culture supernatants was analyzed using ELISA (n=4). (C-F) The growth factor receptor inhibitors (C) erlotinib (10 μM), (D) tepotinib (5 μM), (E) linsitinib (1 μM) or (F) cediranib (1 μM) were applied to Kelly cells for 48 h alone (Ø) or in combination with fucoidans from F.v. (50 μg/ml) or S.l. (50 μg/ml), before ATP levels were determined. ***p<0.001, **p<0.01 for control vs. cells treated with extracts from F.v. or S.l., with one of the growth factor receptor inhibitors or a combination of both; ###p<0.001, #p<0.05, for inhibitor-treated cells vs. cells, which were simultaneously incubated with one of the growth factor receptor inhibitors and one of the fucoidans.

To quantify the amount of growth factors in cell culture supernatants, ELISA were performed. Application of 50 μg/ml F.v. fucoidan significantly increased the release of HGF (by 60%, p<0.001 vs. controls), while the levels of IGF2 were not affected and the release of VEGF was decreased by 25% (p<0.001 vs. controls). In contrast, incubation with 50 μg/ml fucoidan from S.l. reduced the protein levels of HGF, IGF2 or VEGF by 65%, 25% or 49% (p<0.001), respectively, compared to control cells (Figure 4B).

It was also examined if F.v. or S.l. fucoidans altered the effects of growth factor receptor inhibitors in Kelly cells. Similar to the experiments in SH-SY5Y cells, erlotinib, tepotinib, linsitinib and cediranib were used for Kelly cells. After an incubation with one of the inhibitors alone or simultaneously with F.v. or S.l. fucoidans for 48 h, ATP levels were measured. Treatment with erlotinib (10 μM) reduced the number of viable cells by 21% (p<0.001) compared to control cells. Co-administration of 50 μg/ml fucoidans from F.v. or S.l. decreased ATP levels by 33% or 45%, respectively (p<0.001 vs. controls). Only the simultaneous application with the fucoidan from S.l. and erlotinib significantly attenuated ATP levels compared to inhibitor-treated cells (Figure 4C). Incubation with tepotinib (5 μM) did not change ATP levels, while co-treatment with the fucoidans significantly (p<0.001 vs. controls) reduced ATP levels by 46% for the fucoidan from F.v. and by 84% for the fucoidan from S.l., which were also distinctly lower than those observed in tepotinib-treated cells (p<0.001) (Figure 4D). In response to linsitinib (1 μM), ATP levels of Kelly cells were decreased by 25% (p< 0.001) compared to control cells. When 50 μg/ml of the fucoidans from F.v. or S.l. were added, ATP levels were reduced by 34% or 44%, respectively (p<0.001 vs. controls) (Figure 4E). After stimulation with cediranib (1 μM), ATP levels were not affected. Co-treatment with 50 μg/ml of F.v. fucoidan reduced ATP levels by 47% (p< 0.001 vs. controls or cediranib-treated cells). When cediranib and 50 μg/ml of the fucoidan from S.l. were concomitantly applied, viability was decreased by 46% (p< 0.001 vs. controls or cediranib-treated cells) (Figure 4F).

Taken together, despite growth factor-specific differences, the overall effects of the fucoidans on Kelly cells were comparable to those observed in SH-SY5Y cells.

Discussion

Fucose-containing sulfated polysaccharides from brown algae, known as fucoidan, have gained attention for their anticancer properties. However, the degree of their therapeutic potential as well as the proposed mechanisms of action seem to be dependent on the structural characteristics of the fucoidans, the experimental settings and the cellular models (27, 28). For neuroblastoma cells, in particular, there has been no evidence for fucoidan-mediated tumor-suppressive effects, yet (24). In the present study, it was demonstrated that incubation with fucoidans from F.v. and S.l. decreased the levels of ATP of the human neuroblastoma SH-SY5Y or Kelly cells due to impaired growth factor signaling, while the release of HGF, IGF2 or VEGF was differentially regulated in a cell type-specific manner.

For examining putative anticancer effects in neuroblastoma cells, two fucoidans with proven tumor-suppressive properties were chosen. As a commercially available reference standard, fucoidan from F.v. was used, which had been characterized as antiproliferative and even apoptosis-inducing in numerous cancer cell lines (14, 22). To also consider the impact of structure-function relations, the fucoidan from S.l. was included in the experiments, because it had directly been compared with F.v. fucoidan in terms of compositional and structural parameters as well as biological activities (29-33, 41). Similar to the results of the present study, the potential anticancer effects induced by F.v. and S.l. fucoidans were similar, but those of S.l. fucoidan were more pronounced (29, 31, 41).

In the current study, both fucoidans reduced the ATP levels of Kelly and SH-SY5Y cells due to attenuated proliferation, while no cytotoxic reactions were observed. So far, neuroblastoma cells have mostly been treated with fucoidans in proinflammatory or proapoptotic experimental setups to evaluate potential protective effects (25, 26, 42, 43). When SK-N-SE neuroblastoma cells were incubated with extracts from the brown algae Cladosiphon okamuranus (also named Okinawa mozuku), cell growth was not altered after 72 h, whereas the proliferation of hepatocellular carcinoma, cholangiocarcinoma or gallbladder carcinoma cells was attenuated (24). Thus, the susceptibility of neuroblastoma cells to fucoidan treatment, seemed to be dependent on the type of brown algae extract, the neuroblastoma cell line and the experimental settings.

Corresponding to decreased cell growth, the phosphorylation of Akt and ERK1/2 was reduced after incubation with fucoidan from S.l. in SH-SY5Y cells. Both kinases are crucial for cell cycle progression and suppression of apoptosis in malignant cells (44, 45) and the attenuation of their activity has been shown for different fucoidans (14). The S.l. fucoidan used in the present study decreased CXCL12-induced ERK1/2 phosphorylation in Raji cells (33), but its effect on Akt activity has not been examined before. Well-documented are the effects of the fucoidan from F.v., which decreased the activation of Akt in different tumor cell lines, e.g., in AML or breast cancer cells as well as in ovarian, uterine or endometrial carcinoma (46, 47). Similarly, reduced levels of phosphorylated ERK1/2 were detected after treatment with fucoidan from F.v. in several cell lines like AML, lymphoma or breast cancer (46, 48, 49). In SH-SY5Y cells, the fucoidan from F.v. did not affect the phosphorylation of Akt and ERK1/2, although proliferation was reduced, which might result from impaired TGF beta signaling (23), which has not been part of this study.

No cytotoxicity was detected in response to the fucoidans from F.v. or S.l. in both cell lines. Accordingly, JNK phosphorylation was not altered after treatment with both fucoidans. Although the role of JNK in cancer progression is rather complex (50), its activation by fucoidan treatment has been associated with proapoptotic effects in previous studies (51, 52), as shown for the application of at least 800 μg/ml of the F.v. fucoidan, which was much higher compared to the concentrations used in this study (51).

To further examine the growth-inhibitory effects of fucoidan treatment, growth factor signaling was analyzed. While both fucoidans decreased levels of HGF, IGF2 and VEGF in SH-SY5Y cells, only the fucoidan from S.l. reduced the levels of all growth factors in Kelly cells. F.v. fucoidan treatment enhanced HGF release but did not affect the levels of IGF2. The differential effects on HGF release might be cell type-dependent, as fucoidan treatment decreased HGF secretion in hepatocarcinoma cells (40), while HGF levels were increased in embryonic lung fibroblasts or muscle satellite cells (53, 54). However, the different effects might also be fucoidan-specific, as all studies used extracts from different brown algae.

So far, the release of IGF2 has not been examined in response to fucoidan treatment, but it has already been shown that signaling via IGF1R as well as IGF1 expression were inhibited by fucoidan (38, 55). Moreover, the growth inhibitory effect on ovarian carcinoma cells, which had been treated with F.v. fucoidan, could be partly rescued by application of IGF1 (56), which might argue for a fucoidan-mediated impairment on IGF signaling. The fucoidan-altered regulation of VEGF has been examined in different cellular model systems before. As in the present study, VEGF expression and release were decreased by fucoidan treatment, which was also associated with a reduction of cell growth or angiogenesis (49, 57-60).

Since the interaction with the growth factor receptors EGFR, c-Met, IGF1R or VEGFR has been shown for different fucoidans (39, 55, 61, 62), it was analyzed if F.v. or S.l. fucoidans potentiated the effects of growth factor receptor inhibitors. In Kelly and SH-SY5Y cells, the simultaneous application of the fucoidans and erlotinib, tepotinib, linsitinib or cediranib distinctly decreased cellular ATP levels, except for the combination of F.v. fucoidan and erlotinib in Kelly cells. For EGFR signaling, it was shown before that fucoidan treatment acted synergistically with sorafenib by binding the EGF receptor and inhibiting its nuclear localization (63). In Kelly and SH-SY5Y cells, the effects of co-incubation with S.l. fucoidan and erlotinib are in line with the observed effects and suggest a fucoidan-mediated effect on EGFR signaling in neuroblastoma cells.

The interaction between fucoidans and c-Met inhibitors has not been examined before. In hepatocarcinoma cells, fucoidan reduced the amount of c-Met and inhibited Akt and ERK1/2 survival signaling (62). This might explain the significant decrease in cellular ATP levels observed by concomitant incubation with tepotinib in the present study, although F.v. fucoidan even increased HGF release in Kelly cells. Similarly, no inhibitor of IGF1R-mediated signaling has been co-applied with fucoidans, so far. Still, it was observed that IGF1-induced signal transduction was attenuated by fucoidan treatment in colon cancer cells (55), which might contribute to the chemosensitizing effects shown in Kelly and SH-SY5Y cells.

VEGFR-mediated signaling was impaired by fucoidan treatment in different cellular systems by interfering with the interaction of VEGF and its receptors (64-66). Synergistic effects were observed in hepatocellular carcinoma by co-incubation with fucoidan and bevacizumab (67). In the present study, cediranib only had a moderate effect on cellular ATP levels in SH-SY5Y cells, but not on Kelly cells, whereas co-treatment with F.v. or S.l. fucoidans showed strong effects in both cell lines.

Conclusion

Taken together, treatment with F.v. or S.l. fucoidan decreased ATP levels and proliferation in SH-SY5Y and Kelly neuroblastoma cells. Both fucoidans reduced the production of endogenous HGF, IGF2, and VEGF, which might support the effects of specific growth factor receptor inhibitors.

Acknowledgements

The Authors would like to thank Irina Naujoks and Annika Muetze for their excellent technical assistance.

Footnotes

  • Authors’ Contributions

    NW and NSP conducted experiments. MK conducted experiments and reviewed the manuscript. SA provided the fucoidans. IC reviewed and revised the manuscript. VW designed and supervised the study, designed and conducted experiments and wrote the manuscript.

  • Conflicts of Interest

    The Authors declare no conflicts of interest in relation to this study.

  • Funding

    The study received no funding.

  • Artificial Intelligence (AI) Disclosure

    No artificial intelligence (AI) tools, including large language models or machine learning software, were used in the preparation, analysis, or presentation of this manuscript.

  • Received May 5, 2025.
  • Revision received May 12, 2025.
  • Accepted May 13, 2025.

This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).

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Fucoidan Treatment Leads to Attenuated Growth Factor Signaling and Reduced Proliferation in Neuroblastoma Cells
NIKLAS WEBER, NINA SOPHIE POMMERT, MEIKE KAEHLER, INGOLF CASCORBI, SUSANNE ALBAN, VICKI WAETZIG
Anticancer Research Jul 2025, 45 (7) 2749-2762; DOI: 10.21873/anticanres.17644
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