Pioglitazone induces cell growth arrest and activates mitochondrial apoptosis in human uterine leiomyosarcoma cells by a peroxisome proliferator-activated receptor γ-independent mechanism

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• 作者：Ulf Lützen ; Yi Zhao ; Katja Lucht…
• 关键词：Uterine leimysarcoma ; Pioglitazone ; PPARγ ; MAPK ; Cell cycle arrest ; Apoptosis
• 刊名：Naunyn-Schmiedeberg's Archives of Pharmacology
• 出版年：2017
• 出版时间：January 2017
• 年：2017
• 卷：390
• 期：1
• 页码：37-48
• 全文大小：
• 刊物类别：Biomedical and Life Sciences
• 刊物主题：Pharmacology/Toxicology; Neurosciences;
• 出版者：Springer Berlin Heidelberg
• ISSN：1432-1912
• 卷排序：390

文摘

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.