Potent and PPARα-independent anti-proliferative action of the hypolipidemic drug fenofibrate in VEGF-dependent angiosarcomas in vitro

Yasser Majeed, Rohit Upadhyay, Sara Alhousseiny, Tarek Taha, Adham Musthak, Yanal Shaheen, Mohtashim Jameel, Christopher Triggle, Hong Ding

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Angiosarcomas are highly aggressive tumors of endothelial origin, which carry a poor prognosis. Fenofibrate is a hypolipidemic drug, which acts by activating the transcription factor PPARα. It has also been widely reported to have ‘anti-cancer’ activity. The current study investigated its effect in a murine VEGF-dependent angiosarcoma cell-line, MS1 VEGF. The study utilised assays to monitor cell proliferation and viability, apoptosis, cell cycle progression, mitochondrial membrane potential, changes in protein expression, and changes in miRNA expression using microarrays. Fenofibrate showed potent anti-proliferative action in MS1 VEGF angiosarcoma cells, without inducing apoptosis. It enriched cells in G2/M cell cycle phase and hyperpolarised mitochondria. Other PPARα activators failed to mimic fenofibrate action. Inhibitors of PPARα and NFκB failed to reverse the inhibitory effect of fenofibrate and their combination with fenofibrate was cytotoxic. Fenofibrate downregulated the expression of key VEGF-effector proteins, including Akt, ERK, Bcl-2 and survivin, and a chemical inhibitor screen discovered relevance of these proteins to cell proliferation. A miRNA microarray revealed that fenofibrate differentially regulated cellular miRNAs with known roles in cancer and angiogenesis. The data raise the possibility that fenofibrate could be useful in angiosarcoma therapy, especially considering its well-established clinical safety and tolerability profile.

Original languageEnglish
Article number6316
JournalScientific reports
Volume9
Issue number1
DOIs
Publication statusPublished - 1 Dec 2019

Fingerprint

Fenofibrate
Hypolipidemic Agents
Hemangiosarcoma
Peroxisome Proliferator-Activated Receptors
Vascular Endothelial Growth Factor A
MicroRNAs
Cell Cycle
Activating Transcription Factors
Cell Proliferation
Apoptosis
Neoplasms
Proteins
In Vitro Techniques
Mitochondrial Membrane Potential
Cell Survival
Mitochondria
Down-Regulation
Safety
Cell Line

ASJC Scopus subject areas

  • General

Cite this

Potent and PPARα-independent anti-proliferative action of the hypolipidemic drug fenofibrate in VEGF-dependent angiosarcomas in vitro. / Majeed, Yasser; Upadhyay, Rohit; Alhousseiny, Sara; Taha, Tarek; Musthak, Adham; Shaheen, Yanal; Jameel, Mohtashim; Triggle, Christopher; Ding, Hong.

In: Scientific reports, Vol. 9, No. 1, 6316, 01.12.2019.

Research output: Contribution to journalArticle

Majeed, Yasser ; Upadhyay, Rohit ; Alhousseiny, Sara ; Taha, Tarek ; Musthak, Adham ; Shaheen, Yanal ; Jameel, Mohtashim ; Triggle, Christopher ; Ding, Hong. / Potent and PPARα-independent anti-proliferative action of the hypolipidemic drug fenofibrate in VEGF-dependent angiosarcomas in vitro. In: Scientific reports. 2019 ; Vol. 9, No. 1.
@article{8acb61f23a4943f0af776750dd68472c,
title = "Potent and PPARα-independent anti-proliferative action of the hypolipidemic drug fenofibrate in VEGF-dependent angiosarcomas in vitro",
abstract = "Angiosarcomas are highly aggressive tumors of endothelial origin, which carry a poor prognosis. Fenofibrate is a hypolipidemic drug, which acts by activating the transcription factor PPARα. It has also been widely reported to have ‘anti-cancer’ activity. The current study investigated its effect in a murine VEGF-dependent angiosarcoma cell-line, MS1 VEGF. The study utilised assays to monitor cell proliferation and viability, apoptosis, cell cycle progression, mitochondrial membrane potential, changes in protein expression, and changes in miRNA expression using microarrays. Fenofibrate showed potent anti-proliferative action in MS1 VEGF angiosarcoma cells, without inducing apoptosis. It enriched cells in G2/M cell cycle phase and hyperpolarised mitochondria. Other PPARα activators failed to mimic fenofibrate action. Inhibitors of PPARα and NFκB failed to reverse the inhibitory effect of fenofibrate and their combination with fenofibrate was cytotoxic. Fenofibrate downregulated the expression of key VEGF-effector proteins, including Akt, ERK, Bcl-2 and survivin, and a chemical inhibitor screen discovered relevance of these proteins to cell proliferation. A miRNA microarray revealed that fenofibrate differentially regulated cellular miRNAs with known roles in cancer and angiogenesis. The data raise the possibility that fenofibrate could be useful in angiosarcoma therapy, especially considering its well-established clinical safety and tolerability profile.",
author = "Yasser Majeed and Rohit Upadhyay and Sara Alhousseiny and Tarek Taha and Adham Musthak and Yanal Shaheen and Mohtashim Jameel and Christopher Triggle and Hong Ding",
year = "2019",
month = "12",
day = "1",
doi = "10.1038/s41598-019-42838-y",
language = "English",
volume = "9",
journal = "Scientific Reports",
issn = "2045-2322",
publisher = "Nature Publishing Group",
number = "1",

}

TY - JOUR

T1 - Potent and PPARα-independent anti-proliferative action of the hypolipidemic drug fenofibrate in VEGF-dependent angiosarcomas in vitro

AU - Majeed, Yasser

AU - Upadhyay, Rohit

AU - Alhousseiny, Sara

AU - Taha, Tarek

AU - Musthak, Adham

AU - Shaheen, Yanal

AU - Jameel, Mohtashim

AU - Triggle, Christopher

AU - Ding, Hong

PY - 2019/12/1

Y1 - 2019/12/1

N2 - Angiosarcomas are highly aggressive tumors of endothelial origin, which carry a poor prognosis. Fenofibrate is a hypolipidemic drug, which acts by activating the transcription factor PPARα. It has also been widely reported to have ‘anti-cancer’ activity. The current study investigated its effect in a murine VEGF-dependent angiosarcoma cell-line, MS1 VEGF. The study utilised assays to monitor cell proliferation and viability, apoptosis, cell cycle progression, mitochondrial membrane potential, changes in protein expression, and changes in miRNA expression using microarrays. Fenofibrate showed potent anti-proliferative action in MS1 VEGF angiosarcoma cells, without inducing apoptosis. It enriched cells in G2/M cell cycle phase and hyperpolarised mitochondria. Other PPARα activators failed to mimic fenofibrate action. Inhibitors of PPARα and NFκB failed to reverse the inhibitory effect of fenofibrate and their combination with fenofibrate was cytotoxic. Fenofibrate downregulated the expression of key VEGF-effector proteins, including Akt, ERK, Bcl-2 and survivin, and a chemical inhibitor screen discovered relevance of these proteins to cell proliferation. A miRNA microarray revealed that fenofibrate differentially regulated cellular miRNAs with known roles in cancer and angiogenesis. The data raise the possibility that fenofibrate could be useful in angiosarcoma therapy, especially considering its well-established clinical safety and tolerability profile.

AB - Angiosarcomas are highly aggressive tumors of endothelial origin, which carry a poor prognosis. Fenofibrate is a hypolipidemic drug, which acts by activating the transcription factor PPARα. It has also been widely reported to have ‘anti-cancer’ activity. The current study investigated its effect in a murine VEGF-dependent angiosarcoma cell-line, MS1 VEGF. The study utilised assays to monitor cell proliferation and viability, apoptosis, cell cycle progression, mitochondrial membrane potential, changes in protein expression, and changes in miRNA expression using microarrays. Fenofibrate showed potent anti-proliferative action in MS1 VEGF angiosarcoma cells, without inducing apoptosis. It enriched cells in G2/M cell cycle phase and hyperpolarised mitochondria. Other PPARα activators failed to mimic fenofibrate action. Inhibitors of PPARα and NFκB failed to reverse the inhibitory effect of fenofibrate and their combination with fenofibrate was cytotoxic. Fenofibrate downregulated the expression of key VEGF-effector proteins, including Akt, ERK, Bcl-2 and survivin, and a chemical inhibitor screen discovered relevance of these proteins to cell proliferation. A miRNA microarray revealed that fenofibrate differentially regulated cellular miRNAs with known roles in cancer and angiogenesis. The data raise the possibility that fenofibrate could be useful in angiosarcoma therapy, especially considering its well-established clinical safety and tolerability profile.

UR - http://www.scopus.com/inward/record.url?scp=85064562343&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85064562343&partnerID=8YFLogxK

U2 - 10.1038/s41598-019-42838-y

DO - 10.1038/s41598-019-42838-y

M3 - Article

C2 - 31004117

AN - SCOPUS:85064562343

VL - 9

JO - Scientific Reports

JF - Scientific Reports

SN - 2045-2322

IS - 1

M1 - 6316

ER -