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Cited by 14Hippo pathway signaling and YAP/TAZNeuroblastoma Research and TreatmentsCell death mechanisms and regulation

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Verteporfin-induced proteotoxicity impairs cell homeostasis and survival in neuroblastoma subtypes independent of YAP/TAZ expression

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Condurat, Alexandra-Larisa, Aminzadeh-Gohari, Sepideh, Malnar, Mirjana, Schider, Nicole, Opitz, Leonie, Thomas, Ria, Menon, Vishal, Kofler, Barbara, Pruszak, Jan·2023·Scientific Reports
DOI 10.1038/s41598-023-29796-2PMC PMC9992669

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Abstract

Neuroblastoma (NB) is a highly aggressive extracranial solid tumor in children. Due to its heterogeneity, NB remains a therapeutic challenge. Several oncogenic factors, including the Hippo effectors YAP/TAZ, are associated with NB tumorigenesis. Verteporfin (VPF) is an FDA-approved drug shown to directly inhibit YAP/TAZ activity. Our study aimed to investigate VPF’s potential as a therapeutic agent in NB. We show that VPF selectively and efficiently impairs the viability of YAP/TAZ-expressing NB GI-ME-N and SK-N-AS cells, but not of non-malignant fibroblasts. To investigate whether VPF-mediated NB cell killing is YAP-dependent, we tested VPF potency in CRISPR-mediated YAP/TAZ knock-out GI-ME-N cells, and BE(2)-M17 NB cells (a MYCN- amplified, predominantly YAP-negative NB subtype). Our data shows that VPF-mediated NB cell killing is not dependent on YAP expression. Moreover, we determined that the formation of higher molecular weight (HMW) complexes is an early and shared VPF-induced cytotoxic mechanism in both YAP-positive and YAP-negative NB models. The accumulation of HMW complexes, involving STAT3, GM130 and COX IV proteins, impaired cell homeostasis and triggered cell stress and cell death mechanisms. Altogether, our study shows significant in vitro and in vivo VPF-induced suppression of NB growth, making VPF a potential therapeutic candidate against NB.

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Figure 1 YAP/TAZ are highly expressed in neuroblastoma models that phenotypically and molecularly resemble early neural crest cells. (a) Phase-contrast images of hESC-derived neural crest cells (NCC), MYCN-non-amplified (GI-ME-N, SK-N-AS, SH-EP, SH-SY5Y) and MYCN-amplified (BE(2)-M17, IMR-32) metastatic neuroblastoma cell lines; scale bars: 100 µm. (b) Comparative western blot analysis of YAP/TAZ co-expression with neuroblastoma biomarkers (N-MYC, C-MYC), pre-/migratory NCC markers (SOX9/10, PAX3, FOXD3) and neuronal markers (N-CADHERIN, DCX, NCAM, TH, PERIPHERIN) showing a strong overlap of YAP/TAZ expression with early NCC markers. (c) Immunofluorescence analysis of DCX (green) and YAP (red) co-expression in NCC and NB cell lines showing the absence/low expression of YAP in DCX + cells; scale bars: 50 µm. Arrowheads: blue = neuroblast/neuronal-like cell, red = large/mesenchymal-like cell, turquoise = round /low adherent cell.
Figure 1 YAP/TAZ are highly expressed in neuroblastoma models that phenotypically and molecularly resemble early neural crest cells. (a) Phase-contrast images of hESC-derived neural crest cells (NCC), MYCN-non-amplified (GI-ME-N, SK-N-AS, SH-EP, SH-SY5Y) and MYCN-amplified (BE(2)-M17, IMR-32) metastatic neuroblastoma cell lines; scale bars: 100 µm. (b) Comparative western blot analysis of YAP/TAZ co-expression with neuroblastoma biomarkers (N-MYC, C-MYC), pre-/migratory NCC markers (SOX9/10, PAX3, FOXD3) and neuronal markers (N-CADHERIN, DCX, NCAM, TH, PERIPHERIN) showing a strong overlap of YAP/TAZ expression with early NCC markers. (c) Immunofluorescence analysis of DCX (green) and YAP (red) co-expression in NCC and NB cell lines showing the absence/low expression of YAP in DCX + cells; scale bars: 50 µm. Arrowheads: blue = neuroblast/neuronal-like cell, red = large/mesenchymal-like cell, turquoise = round /low adherent cell.CC BY · PubMed Central
Figure 2 Verteporfin is a potent and selective therapeutic agent in GI-ME-N YAP-expressing neuroblastoma cells. (a) Phase-contrast images of GI-ME-N cells treated for 3 consecutive days with various compounds (n = 4; DMSO = vehicle control; RA = retinoic acid, 10 µM; VPA = valproic acid, 2 mM; Dob = dobutamine, 20 µM; VPF = verteporfin, 10 µM; MvS = mevastatin, 10 µM; SvS = simvastatin, 10 µM; CvS = cerivastatin, 10 µM; CV = crystal violet viability staining at day 3 post-treatment). (b) Corresponding quantification of viable GI-ME-N cells by crystal violet staining following the 3 days treatment. Bars represent average ± SEM (n = 4; normalized against DMSO controls set to 100%), statistical significance was determined using a one-way analysis of variance (ANOVA) with Dunnett’s post-hoc test: ns = not statistically significant; **p ≤ 0.01; ***p ≤ 0.001. Indirect immunofluorescence of YAP expression in GI-ME-N NB cells (c) and non-malignant fetal fibroblasts—D551 cells (d), highlighting a strong YAP nuclear localization in both cell systems; scale bars: 50 µm. Cell viability assessed by crystal violet (CV) staining of 3 days-treated GI-ME-N cells (e) and D551 fibroblasts (f) with increased concentrations of VPF and the corresponding quantification. DMSO treatment was used as a vehicle control. Bars represent average ± SEM (n ≥ 4; normalized against DMSO controls set to 100%), statistical significance was determined using a two-way analysis of variance (ANOVA) followed by Bonferroni’s post-hoc test: ns = not statistically significant; *p ≤ 0.05; **p ≤ 0.01; ***p ≤ 0.001.
Figure 2 Verteporfin is a potent and selective therapeutic agent in GI-ME-N YAP-expressing neuroblastoma cells. (a) Phase-contrast images of GI-ME-N cells treated for 3 consecutive days with various compounds (n = 4; DMSO = vehicle control; RA = retinoic acid, 10 µM; VPA = valproic acid, 2 mM; Dob = dobutamine, 20 µM; VPF = verteporfin, 10 µM; MvS = mevastatin, 10 µM; SvS = simvastatin, 10 µM; CvS = cerivastatin, 10 µM; CV = crystal violet viability staining at day 3 post-treatment). (b) Corresponding quantification of viable GI-ME-N cells by crystal violet staining following the 3 days treatment. Bars represent average ± SEM (n = 4; normalized against DMSO controls set to 100%), statistical significance was determined using a one-way analysis of variance (ANOVA) with Dunnett’s post-hoc test: ns = not statistically significant; **p ≤ 0.01; ***p ≤ 0.001. Indirect immunofluorescence of YAP expression in GI-ME-N NB cells (c) and non-malignant fetal fibroblasts—D551 cells (d), highlighting a strong YAP nuclear localization in both cell systems; scale bars: 50 µm. Cell viability assessed by crystal violet (CV) staining of 3 days-treated GI-ME-N cells (e) and D551 fibroblasts (f) with increased concentrations of VPF and the corresponding quantification. DMSO treatment was used as a vehicle control. Bars represent average ± SEM (n ≥ 4; normalized against DMSO controls set to 100%), statistical significance was determined using a two-way analysis of variance (ANOVA) followed by Bonferroni’s post-hoc test: ns = not statistically significant; *p ≤ 0.05; **p ≤ 0.01; ***p ≤ 0.001.CC BY · PubMed Central
Figure 3 Verteporfin downregulates the expression of oncogenic, pro-survival and cell-cycle modulators and drives the activation of cell stress and cell death effectors. (a) Representative phase-contrast images of GI-ME-N cells treated for 24 h with DMSO, 2 µM or 5 µM VPF; scale bar: 100 µm. Western blot analysis of GI-ME-N cells treated for 24 h with either 2 or 5 µM VPF shows the downregulation of oncogenic and pro-survival mediators (b), downregulation of cell cycle modulators (c) and activation of cell stress and cell death mediators (d), compared to the DMSO control. Moreover, VPF-treated GI-ME-N cells indicate the formation of COX IV (red) higher molecular weight complexes. (e) Immunofluorescence analysis of GI-ME-N cells treated for 48 h with 5 µM VPF illustrate a reduction of YAP expression and Ki67-positive cells, as well as the activation of cell-stress mediators phospho-Ser82-HSP27 and ATG16L1; scale bars: 50 µm.
Figure 3 Verteporfin downregulates the expression of oncogenic, pro-survival and cell-cycle modulators and drives the activation of cell stress and cell death effectors. (a) Representative phase-contrast images of GI-ME-N cells treated for 24 h with DMSO, 2 µM or 5 µM VPF; scale bar: 100 µm. Western blot analysis of GI-ME-N cells treated for 24 h with either 2 or 5 µM VPF shows the downregulation of oncogenic and pro-survival mediators (b), downregulation of cell cycle modulators (c) and activation of cell stress and cell death mediators (d), compared to the DMSO control. Moreover, VPF-treated GI-ME-N cells indicate the formation of COX IV (red) higher molecular weight complexes. (e) Immunofluorescence analysis of GI-ME-N cells treated for 48 h with 5 µM VPF illustrate a reduction of YAP expression and Ki67-positive cells, as well as the activation of cell-stress mediators phospho-Ser82-HSP27 and ATG16L1; scale bars: 50 µm.CC BY · PubMed Central
Figure 4 Short verteporfin treatment is sufficient to disrupt cell homeostasis via the formation of proteotoxic higher molecular weight complexes. (a) Western blot analysis of GI-ME-N cells treated for 30 min (30’) or 1 h with 5 µM VPF shows marked downregulation of pro-survival and migratory molecules (α4-/β1-integrin subunits), transcription modulators (STAT3, β-CATENIN, C-MYC), cell cycle factors (CYCLIN D1, CDK2), and activation of cell stress mechanisms (activating phosphorylation of p38, HSP27), and formation of COX IV higher molecular weight complexes—HMW (red). (b) Western blot analysis of GI-ME-N cells treated for 30’or 24 h with 5 µM VPF shows the formation and accumulation of GM130 and STAT3 HMW. (c) Immunofluorescence images of GI-ME-N cells treated for 24 h with 5 µM VPF highlighting the altered subcellular appearance of COX IV and GM130, respectively; scale bars: 50 µm. CD44 and CD29 surface antigen immunodetection was used as cell membrane counterstaining.
Figure 4 Short verteporfin treatment is sufficient to disrupt cell homeostasis via the formation of proteotoxic higher molecular weight complexes. (a) Western blot analysis of GI-ME-N cells treated for 30 min (30’) or 1 h with 5 µM VPF shows marked downregulation of pro-survival and migratory molecules (α4-/β1-integrin subunits), transcription modulators (STAT3, β-CATENIN, C-MYC), cell cycle factors (CYCLIN D1, CDK2), and activation of cell stress mechanisms (activating phosphorylation of p38, HSP27), and formation of COX IV higher molecular weight complexes—HMW (red). (b) Western blot analysis of GI-ME-N cells treated for 30’or 24 h with 5 µM VPF shows the formation and accumulation of GM130 and STAT3 HMW. (c) Immunofluorescence images of GI-ME-N cells treated for 24 h with 5 µM VPF highlighting the altered subcellular appearance of COX IV and GM130, respectively; scale bars: 50 µm. CD44 and CD29 surface antigen immunodetection was used as cell membrane counterstaining.CC BY · PubMed Central
Figure 5 Verteporfin efficiently targets BE(2)-M17 cells, a predominantly YAP-negative and MYCN-amplified NB subtype. (a) Western blot analysis of BE(2)-M17 cells treated for 24 h with either 2 or 5 µM VPF, showing the downregulation of transcriptional regulators (N-MYC, STAT3) and cell cycle progression factors (CDK2/4/6), the upregulation of cell death regulators (cleaved PARP, cleaved caspase-3) and the formation of COX IV HMW complexes (red). (b) Western blot analysis of BE(2)-M17 cells treated for 30 min (30’) or 24 h with 5 µM VPF shows the formation and accumulation of GM130 and STAT3 high-molecular weight protein complexes. (c) Representative images of viable BE(2)-M17 cells after 1 to 3 days of 5 µM VPF treatment, as assessed by crystal violet staining, and the corresponding quantification graph. Data is represented as average ± SEM (n = 5; normalized against DMSO controls set to 100%). Two-way analysis of variance (ANOVA) followed by Bonferroni post-hoc tests was used to assess statistical significance (**p ≤ 0.01; ***p ≤ 0.001).
Figure 5 Verteporfin efficiently targets BE(2)-M17 cells, a predominantly YAP-negative and MYCN-amplified NB subtype. (a) Western blot analysis of BE(2)-M17 cells treated for 24 h with either 2 or 5 µM VPF, showing the downregulation of transcriptional regulators (N-MYC, STAT3) and cell cycle progression factors (CDK2/4/6), the upregulation of cell death regulators (cleaved PARP, cleaved caspase-3) and the formation of COX IV HMW complexes (red). (b) Western blot analysis of BE(2)-M17 cells treated for 30 min (30’) or 24 h with 5 µM VPF shows the formation and accumulation of GM130 and STAT3 high-molecular weight protein complexes. (c) Representative images of viable BE(2)-M17 cells after 1 to 3 days of 5 µM VPF treatment, as assessed by crystal violet staining, and the corresponding quantification graph. Data is represented as average ± SEM (n = 5; normalized against DMSO controls set to 100%). Two-way analysis of variance (ANOVA) followed by Bonferroni post-hoc tests was used to assess statistical significance (**p ≤ 0.01; ***p ≤ 0.001).CC BY · PubMed Central
Figure 6 Verteporfin efficiently suppresses in vitro and in vivo SH-SY5Y neuroblastoma cell survival and tumor growth. (a) Crystal violet staining of viable SH-SY5Y cells after 1 to 3 days of 1 or 5 µM VPF treatment and the corresponding quantification graphs. Data is represented as average ± SEM (n = 4; normalized against DMSO controls set to 100%). Two-way analysis of variance (ANOVA) followed by Bonferroni post-hoc tests was used to assess the statistical significance (***p ≤ 0.001). (b) Representative images of SH-SY5Y NB xenografts isolated from mice treated with vehicle or 100 mg/kg VPF. (c) Graphical representation of tumor volume in control, vehicle-treated, group (dark blue) and 100 mg/kg VPF-treated group (light blue). Data represented as average ± SEM (n = 7 control group, n = 8 VPF-treated). Statistical significance was calculated using the two-way repeated measures ANOVA test (*p ≤ 0.05; **p ≤ 0.01).
Figure 6 Verteporfin efficiently suppresses in vitro and in vivo SH-SY5Y neuroblastoma cell survival and tumor growth. (a) Crystal violet staining of viable SH-SY5Y cells after 1 to 3 days of 1 or 5 µM VPF treatment and the corresponding quantification graphs. Data is represented as average ± SEM (n = 4; normalized against DMSO controls set to 100%). Two-way analysis of variance (ANOVA) followed by Bonferroni post-hoc tests was used to assess the statistical significance (***p ≤ 0.001). (b) Representative images of SH-SY5Y NB xenografts isolated from mice treated with vehicle or 100 mg/kg VPF. (c) Graphical representation of tumor volume in control, vehicle-treated, group (dark blue) and 100 mg/kg VPF-treated group (light blue). Data represented as average ± SEM (n = 7 control group, n = 8 VPF-treated). Statistical significance was calculated using the two-way repeated measures ANOVA test (*p ≤ 0.05; **p ≤ 0.01).CC BY · PubMed Central
Figure 7 Verteporfin YAP-independent oncosuppressive effects in neuroblastoma. Schematic illustration of VPF-induced molecular and phenotypic effects, including downregulation of oncogenic factors—YAP/TAZ/MYC/N-MYC, oncogenic signaling cascades—ERK1/2/STAT3 signaling, and formation of high molecular weight complexes—HMW, leading to impaired cell proliferation, migration and survival, loss of cell homeostasis, activation of cell stress and cell death mechanisms. RTKs—Receptor Tyrosine Kinases; VPF—Verteporfin; ROS—Reactive Oxygen Species.
Figure 7 Verteporfin YAP-independent oncosuppressive effects in neuroblastoma. Schematic illustration of VPF-induced molecular and phenotypic effects, including downregulation of oncogenic factors—YAP/TAZ/MYC/N-MYC, oncogenic signaling cascades—ERK1/2/STAT3 signaling, and formation of high molecular weight complexes—HMW, leading to impaired cell proliferation, migration and survival, loss of cell homeostasis, activation of cell stress and cell death mechanisms. RTKs—Receptor Tyrosine Kinases; VPF—Verteporfin; ROS—Reactive Oxygen Species.CC BY · PubMed Central

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Metadata

Authors
Condurat, A.-L., Aminzadeh-Gohari, S., Malnar, M., Schider, N., Opitz, L., Thomas, R., Menon, V., Kofler, B., & Pruszak, J.
Affiliations
  • University of Freiburg (DE)
  • Paracelsus Medical University (AT)
Corresponding author
Pruszak, Jan
ORCID
Venue
Scientific Reports
Publisher
Springer Science and Business Media LLC
Published
2023-03-07
Volume
13
Issue
1
Pages
3760-3760
ISSN
2045-2322 (ISSN-L)
DOI
10.1038/s41598-023-29796-2
PMC
PMC9992669
OpenAlex
W4323359919
Cited by
14
References
2
Citations by year
2026: 5 · 2025: 4 · 2024: 4 · 2023: 1
FWCI
2.02
Type
journal article
Language
en
Open access
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  • Scientific Reports (publishedVersion, cc-by)
  • Research Square (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion, other-oa)
  • Pure Amsterdam UMC (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Excellence Initiative of the German Research Foundation
  • Faculty of Medicine – University of Freiburg
  • Austrian Science Fund (P31228-B33)
  • German Research Foundation Emmy Noether (PR1132/3-1)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hippo pathway signaling and YAP/TAZ
  • Health Sciences › Medicine › Oncology › Neuroblastoma Research and Treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
Keywords
verteporfin, neuroblastoma, YAP/TAZ, proteotoxicity, high molecular weight protein complexes, STAT3, GM130, cytochrome c oxidase subunit IV, cellular stress, cell death, MYCN-amplified neuroblastoma, cellular homeostasis, drug repurposing
MeSH terms
Verteporfin, Child, Homeostasis, Humans, Neuroblastoma, Carcinogenesis

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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