Pioglitazone induces cell growth arrest and activates mitochondrial apoptosis in human uterine leiomyosarcoma cells by a peroxisome proliferator-activated receptor γ-independent mechanism.
The peroxisome proliferator-activated receptor γ (PPARγ) agonists, thiazolidinediones, including pioglitazone (PIO) exhibit anti-tumour activities in cancer cells. The present study investigates the effects of PIO on cell proliferation and apoptosis in SK-UT-1 cells, a human uterine leiomyosarcoma cell line, and human uterine smooth muscle cells (HUtSMC). The proliferation and viability of SK-UT-1 cells treated with vehicle or PIO were assessed by cell counting and WST-1 assay. The activity of MEK/ERK and p38 MAPK signalling pathways and the expression of p53, the cyclin-dependent kinase inhibitor, p21, Bax, Bad and Bim proteins and cleaved caspase-3 were analysed by Western blotting. Quiescent SK-UT-1 cells intensively proliferate and display high levels of phosphorylated, activated MEK1/2, ERK1/2 and p38 MAPK. PIO (10 or 25 μM) induced time- and dose-dependently cell-growth arrest, reduced the cell numbers and effectively suppressed the over-activated MEK/ERK and p38 MAPK signalling pathways as evidenced by the abolished levels of phosphorylated MEK1/2, ERK1/2 and p38 MAPK. PIO activated the intrinsic apoptotic pathway, i.e. up-regulated the p53, p21, Bax and Bad proteins and cleaved caspase-3. PIO also reduced cell numbers of highly proliferative SK-UT-1 cells cultured in growth medium. The anti-proliferative and pro-apoptotic actions of PIO were not PPARγ dependent and exclusive for SK-UT-1 cells as PIO did not interfere with the proliferation of HUtSMC. The pronounced anti-tumorigenic effects of PIO in SK-UT-1 cells address an important issue about the relevance of the PPARγ agonist in the treatment of the human uterine leiomyosarcoma.
Department of Nuclear Medicine, Molecular Imaging, Diagnostics and Therapy, University Hospital of Schleswig-Holstein, Campus Kiel, Feldstrasse 21, 24105, Kiel, Germany.
Ulf
U
Lützen
Department of Nuclear Medicine, Molecular Imaging, Diagnostics and Therapy, University Hospital of Schleswig-Holstein, Campus Kiel, Feldstrasse 21, 24105, Kiel, Germany.
Yi
Y
Zhao
Institute of Experimental and Clinical Pharmacology, University Hospital of Schleswig-Holstein, Campus Kiel, Hospitalstrasse 4, 24105, Kiel, Germany.
Katja
K
Lucht
Department of Nuclear Medicine, Molecular Imaging, Diagnostics and Therapy, University Hospital of Schleswig-Holstein, Campus Kiel, Feldstrasse 21, 24105, Kiel, Germany.
Maaz
M
Zuhayra
Department of Nuclear Medicine, Molecular Imaging, Diagnostics and Therapy, University Hospital of Schleswig-Holstein, Campus Kiel, Feldstrasse 21, 24105, Kiel, Germany.
Marlies
M
Marx
Institute of Experimental and Clinical Pharmacology, University Hospital of Schleswig-Holstein, Campus Kiel, Hospitalstrasse 4, 24105, Kiel, Germany.
Ingolf
I
Cascorbi
Institute of Experimental and Clinical Pharmacology, University Hospital of Schleswig-Holstein, Campus Kiel, Hospitalstrasse 4, 24105, Kiel, Germany. juraj.culman@pharmakologie.uni-kiel.de.
Juraj
J
Culman
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000187:drug effects*; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D005260:Female; D006801:Humans; D007890:Leiomyosarcoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D047495:PPAR gamma / Q000819:agonists* / Q000378:metabolism; D010766:Phosphorylation; D000077205:Pioglitazone; D015398:Signal Transduction / Q000187:drug effects; D045162:Thiazolidinediones / Q000494:pharmacology*; D013997:Time Factors; D014594:Uterine Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology
D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D018797:Cell Cycle Proteins; D047495:PPAR gamma; D045162:Thiazolidinediones; D020928:Mitogen-Activated Protein Kinases; D000077205:Pioglitazone
Apoptosis; Cell cycle arrest; MAPK; PPARγ; Pioglitazone; Uterine leimysarcoma
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