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 language | English |
|---|---|
| Article number | 6316 |
| Journal | Scientific reports |
| Volume | 9 |
| Issue number | 1 |
| DOIs | |
| Publication status | Published - 1 Dec 2019 |
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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 journal › Article
}
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.
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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
VL - 9
JO - Scientific Reports
JF - Scientific Reports
SN - 2045-2322
IS - 1
M1 - 6316
ER -