Hyperforin induces apoptosis through extrinsic/intrinsic pathways and inhibits <scp>EGFR</scp>/<scp>ERK</scp>/<scp>NF‐κB</scp>‐mediated anti‐apoptotic potential in glioblastoma

Hsu, Fei‐Ting; Chen, Wei‐Ting; Wu, Ching‐Te; Chung, Jing‐Gung

doi:10.1002/tox.22942

Cited by 17 publications

(18 citation statements)

References 36 publications

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“…Similar to PI3K-Akt pathway, MEK-ERK signaling has also been considered as a therapeutic target of glioblastoma. Ethyl pyruvate [52], trametinib [53], amentoflavone [54], hyperforin [55], berberine [56], imipramine [57], and protein neddylation inhibitor MLN4924 [58] inhibit glioblastoma cells migration and invasion via suppressing MEK-ERK pathway. Among them, several drugs have been applied in clinical trials such as trametinib (ClinicalTrials.gov Identifier: NCT03363217) [53].…”

Section: Discussionmentioning

confidence: 99%

Extracellular vesicles derived from glioblastoma promote proliferation and migration of neural progenitor cells via PI3K-Akt pathway

Pan

Sheng

et al. 2022

Cell Commun Signal

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Background Glioblastomas are lethal brain tumors under the current combinatorial therapeutic strategy that includes surgery, chemo- and radio-therapies. Extensive changes in the tumor microenvironment is a key reason for resistance to chemo- or radio-therapy and frequent tumor recurrences. Understanding the tumor-nontumor cell interaction in TME is critical for developing new therapy. Glioblastomas are known to recruit normal cells in their environs to sustain growth and encroachment into other regions. Neural progenitor cells (NPCs) have been noted to migrate towards the site of glioblastomas, however, the detailed mechanisms underlying glioblastoma-mediated NPCs’ alteration remain unkown. Methods We collected EVs in the culture medium of three classic glioblastoma cell lines, U87 and A172 (male cell lines), and LN229 (female cell line). U87, A172, and LN229 were co-cultured with their corresponding EVs, respectively. Mouse NPCs (mNPCs) were co-cultured with glioblastoma-derived EVs. The proliferation and migration of tumor cells and mNPCs after EVs treatment were examined. Proteomic analysis and western blotting were utilized to identify the underlying mechanisms of glioblastoma-derived EVs-induced alterations in mNPCs. Results We first show that glioblastoma cell lines U87-, A172-, and LN229-derived EVs were essential for glioblastoma cell prolifeartion and migration. We then demonstrated that glioblastoma-derived EVs dramatically promoted NPC proliferation and migration. Mechanistic studies identify that glioblastoma-derived EVs achieve their functions via activating PI3K-Akt-mTOR pathway in mNPCs. Inhibiting PI3K-Akt pathway reversed the elevated prolfieration and migration of glioblastoma-derived EVs-treated mNPCs. Conclusion Our findings demonstrate that EVs play a key role in intercellular communication in tumor microenvironment. Inhibition of the tumorgenic EVs-mediated PI3K-Akt-mTOR pathway activation might be a novel strategy to shed light on glioblastoma therapy.

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Section: Discussionmentioning

confidence: 99%

Extracellular vesicles derived from glioblastoma promote proliferation and migration of neural progenitor cells via PI3K-Akt pathway

Pan

Sheng

et al. 2022

Cell Commun Signal

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“…Merhi et al showed [ 30 ] a suppression of protein kinase B (AKT) activity in human myeloid cells at HPF concentrations similar to those used in the present work, whereas Hsu et al proved that HPF can inhibit the extracellular signal-regulated kinases (ERK)-1/2 activity in glioblastoma cells [ 56 ]. Regarding pERK1/2 and pAKT, which are both constitutively active in the BRAF-mutated melanoma cell lines, no different expression levels were found at short times (not shown) and after 24 h treatment in A375 and SK-Mel-28 cells ( Figure 6 C).…”

Section: Resultsmentioning

confidence: 64%

Hyperforin Elicits Cytostatic/Cytotoxic Activity in Human Melanoma Cell Lines, Inhibiting Pro-Survival NF-κB, STAT3, AP1 Transcription Factors and the Expression of Functional Proteins Involved in Mitochondrial and Cytosolic Metabolism

Cardile

Zanrè

Campagnari

et al. 2023

IJMS

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Hyperforin (HPF), the main component responsible for the antidepressant action of Hypericum perforatum, displays additional beneficial properties including anti-inflammatory, antimicrobic, and antitumor activities. Among its antitumor effects, HPF activity on melanoma is poorly documented. Melanoma, especially BRAF-mutated melanoma, is still a high-mortality tumor type and the currently available therapies do not provide solutions. We investigated HPF’s antimelanoma effectiveness in A375, FO1 and SK-Mel-28 human BRAF-mutated cell lines. Cell viability assays documented that all melanoma cells were affected by low HPF concentrations (EC50% 2–4 µM) in a time-dependent manner. A Br-deoxy-uridine incorporation assay attested a significant reduction of cell proliferation accompanied by decreased expression of cyclin D1 and A2, CDK4 and of the Rb protein phosphorylation, as assessed by immunoblots. In addition, the expression of P21/waf1 and the activated form of P53 were increased in A375 and SK-Mel-28 cells. Furthermore, HPF exerts cytotoxic effects. Apoptosis is induced 24 h after HPF administration, documented by an increase of cleaved-PARP1 and a decrease of both Bcl2 and Bcl-xL expression levels. Autophagy is induced, attested by an augmented LC3B expression and augmentation of the activated form of AMPK. Moreover, HPF lowers GPX4 enzyme expression, suggesting ferroptosis induction. HPF has been reported to activate the TRPC6 Ca++ channel and/or Ca++ and Zn++ release from mitochondria stores, increasing cytosolic Ca++ and Zn++ concentrations. Our data highlighted that HPF affects many cell-signaling pathways, including signaling induced by Ca++, such as FRA1, pcJun and pCREB, the expression or activity of which are increased shortly after treatment. However, the blockage of the TRPC6 Ca++ channel or the use of Ca++ and Zn++ chelators do not hinder HPF cytostatic/cytotoxic activity, suggesting that damages induced in melanoma cells may pass through other pathways. Remarkably, 24 h after HPF treatment, the expression of activated forms of the transcription factors NF-κB P65 subunit and STAT3 are significantly lowered. Several cytosolic (PGM2, LDHA and pPKM2) and mitochondrial (UQCRC1, COX4 and ATP5B) enzymes are downregulated by HPF treatment, suggesting a generalized reduction of vital functions in melanoma cells. In line with these results is the recognized ability of HPF to affect mitochondrial membrane potential by acting as a protonophore. Finally, HPF can hinder both melanoma cell migration and colony formation in soft agar. In conclusion, we provide evidence of the pleiotropic antitumor effects induced by HPF in melanoma cells.

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“…Similar to PI3K-Akt pathway, ERK signaling has also been considered as a therapeutic target of glioblastoma. Ethyl pyruvate [52], trametinib [53], amento avone [54], hyperforin [55], berberine [56], imipramine [57], and protein neddylation inhibitor MLN4924 [58] inhibit glioblastoma cells migration and invasion via suppressing ERK pathway. Among them, several drugs has been applied in clinical trials such as trametinib (ClinicalTrials.gov Identi er: NCT03363217) [53].…”

Section: Discussionmentioning

confidence: 99%

Extracellular Vesicles Derived from Glioblastoma Promote Proliferation and Migration of Neural Progenitor Cells via PI3K-Akt Pathway

Pan

Sheng

et al. 2021

Preprint

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BackgroundGlioblastomas are lethal brain tumors under the current combinatorial therapeutic strategy that includes surgery, chemo- and radio-therapies. Extensive changes in the tumor microenvironment is a key reason for resistance to chemo- or radio-therapy and frequent tumor recurrences. Understanding the tumor-nontumor cell interaction in TME is critical for developing new therapy. Glioblastomas are known to recruit normal cells in their environs to sustain growth and encroachment into other regions. Neural progenitor cells (NPCs) have been noted to migrate towards the site of glioblastomas, however, the detailed mechanisms underlying glioblastoma-mediated NPCs’ alteration remain unkown. MethodsWe utilized two classic glioblastoma cell lines, U87- and A172, and collected EVs in the culture medium of those two lines. Mouse NPCs (mNPCs) were co-cultured with U87- or A172-derived EVs. EVs-treated mNPCs’ prolifeartion and migration were examined. Proteomic analysis and western-blot were utilized to identify the underlying mechanisms of glioblastoma EVs-induced alterations in mNPCs.ResultsWe show that glioblastoma cell lines U87- and A172-derived EVs dramatically promoted NPCs proliferation and migration. Mechanistic studies identify that EVs achieve their functions via activating PI3K-Akt-mTOR pathway in recipient cells. Inhibiting PI3K-Akt reversed the elevated prolfieration and migration of glioblastoma EVs-treated mNPCs. ConclusionOur findings demonstrate that EVs play a key role in intercellular communication in tumor microenvironment. Inhibition of the tumorgenic EVs-mediated PI3K-Akt-mTOR pathway activation might be a novel strategy to shed light on glioblastoma therapy.

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Hyperforin induces apoptosis through extrinsic/intrinsic pathways and inhibits EGFR/ERK/NF‐κB‐mediated anti‐apoptotic potential in glioblastoma

Cited by 17 publications

References 36 publications

Extracellular vesicles derived from glioblastoma promote proliferation and migration of neural progenitor cells via PI3K-Akt pathway

Extracellular vesicles derived from glioblastoma promote proliferation and migration of neural progenitor cells via PI3K-Akt pathway

Hyperforin Elicits Cytostatic/Cytotoxic Activity in Human Melanoma Cell Lines, Inhibiting Pro-Survival NF-κB, STAT3, AP1 Transcription Factors and the Expression of Functional Proteins Involved in Mitochondrial and Cytosolic Metabolism

Extracellular Vesicles Derived from Glioblastoma Promote Proliferation and Migration of Neural Progenitor Cells via PI3K-Akt Pathway

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