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

• Published in: Naunyn-Schmiedeberg's archives of pharmacology Vol. 390; no. 1; pp. 37 - 48
• Main Authors: Lützen, Ulf, Zhao, Yi, Lucht, Katja, Zuhayra, Maaz, Marx, Marlies, Cascorbi, Ingolf, Culman, Juraj
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 2017
• Subjects: Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Apoptosis Regulatory Proteins - metabolism; Biomedical and Life Sciences; Biomedicine; Cell Cycle Checkpoints - drug effects; Cell Cycle Proteins - metabolism; Cell Line, Tumor; Cell Proliferation - drug effects; Cell Survival - drug effects; Dose-Response Relationship, Drug; Enzyme Activation; Female; Humans; Leiomyosarcoma - drug therapy; Leiomyosarcoma - metabolism; Leiomyosarcoma - pathology; Mitochondria - drug effects; Mitochondria - metabolism; Mitochondria - pathology; Mitogen-Activated Protein Kinases - metabolism; Neurosciences; Original Article; Pharmacology/Toxicology; Phosphorylation; PPAR gamma - agonists; PPAR gamma - metabolism; Signal Transduction - drug effects; Thiazolidinediones - pharmacology; Time Factors; Uterine Neoplasms - drug therapy; Uterine Neoplasms - metabolism; Uterine Neoplasms - pathology; Cell cycle arrest; Uterine leimysarcoma; MAPK; Pioglitazone; PPARγ; Apoptosis
• ISSN: 0028-1298; 1432-1912
• DOI: 10.1007/s00210-016-1291-x

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.