Comparison of cell cycle components, apoptosis and cytoskeleton-related molecules and therapeutic effects of flavopiridol and geldanamycin on the mouse fibroblast, lung cancer and embryonic stem cells.
Similarities and differences in the cell cycle components, apoptosis and cytoskeleton-related molecules among mouse skin fibroblast cells (MSFs), mouse squamous cell lung carcinomas (SqCLCs) and mouse embryonic stem cells (mESCs) are important determinants of the behaviour and differentiation capacity of these cells. To reveal apoptotic pathways and to examine the distribution and the role of cell cycle-cell skeleton comparatively would necessitate tumour biology and stem cell biology to be assessed together in terms of oncogenesis and embryogenesis. The primary objectives of this study are to investigate the effects of flavopiridol, a cell cycle inhibitor, and geldanamycin, a heat shock protein inhibitor on mouse somatic, tumour and embryonic stem cells, by specifically focusing on alterations in cytoskeletal proteins, cell polarity and motility as well as cell cycle regulators. To meet these objectives, expression of several genes, cell cycle analysis and immunofluorescence staining of intracellular cytoskeletal molecules were performed in untreated and flavopiridol- or geldanamycin-treated cell lines. Cytotoxicity assays showed that SqCLCs are more sensitive to flavopiridol than MSFs and mESCs. Keratin-9 and keratin-2 expressions increased dramatically whereas cell cycle regulatory genes decreased significantly in the flavopiridol-treated MSFs. Flavopiridol-treated SqCLCs displayed a slight increase in several cell cytoskeleton regulatory genes as well as cell cycle regulatory genes. However, gene expression profiles of mESCs were not affected after flavopiridol treatment except the Cdc2a. Cytotoxic concentrations of geldanamycin were close to each other for all cell lines. Cdkn1a was the most increased gene in the geldanamycin-treated MSFs. However, expression levels of cell cytoskeleton-associated genes were increased dramatically in the geldanamycin-treated SqCLCs. Our results revealing differences in molecular mechanisms between embryogenesis and carcinogenesis may prove crucial in developing novel therapeutics that specifically target cancer cells.
Department of Histology and Embryology, Faculty of Medicine, Ege University, Izmir, Turkey.
Huseyin
H
Aktug
Department of Histology and Embryology, Faculty of Medicine, Yuzuncu Yil University, Van, Turkey.
Eda
E
Acikgoz
Department of Histology and Embryology, Faculty of Medicine, Ege University, Izmir, Turkey.
Aysegul
A
Uysal
Department of Histology and Embryology, Faculty of Medicine, Ege University, Izmir, Turkey.
Fatih
F
Oltulu
Department of Histology and Embryology, Faculty of Medicine, Ege University, Izmir, Turkey.
Gulperi
G
Oktem
Department of Histology and Embryology, Faculty of Medicine, Ege University, Izmir, Turkey.
Gurkan
G
Yigitturk
Department of Histology and Embryology, Faculty of Medicine, Ege University, Izmir, Turkey.
Kenan
K
Demir
Department of Histology and Embryology, Faculty of Medicine, Ege University, Izmir, Turkey.
Altug
A
Yavasoglu
Department of Medical Biology, Faculty of Medicine, Ege University, Izmir, Turkey. vildanbcetintas@gmail.com.
Vildan
V
Bozok Cetintas
D000199:Actins / Q000032:analysis; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D016227:Benzoquinones / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D053595:Embryonic Stem Cells / Q000187:drug effects*; D058750:Epithelial-Mesenchymal Transition; D005347:Fibroblasts / Q000187:drug effects; D005419:Flavonoids / Q000494:pharmacology* / Q000627:therapeutic use; D053557:Keratin-2 / Q000032:analysis; D047029:Lactams, Macrocyclic / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D010880:Piperidines / Q000494:pharmacology* / Q000627:therapeutic use
D000199:Actins; D016227:Benzoquinones; D005419:Flavonoids; D053557:Keratin-2; D047029:Lactams, Macrocyclic; D010880:Piperidines; C077990:alvocidib; C001277:geldanamycin
Cell cycle; Cell cycle inhibitor; Cell cytoskeleton; Flavopiridol; Geldanamycin; Heat shock protein inhibitor; Mouse embryonic stem cell; Mouse skin fibroblast cells; Mouse squamous cell lung carcinomas