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


AKTUĞ H. , Açıkgöz E. , UYSAL A. , OLTULU F. , ÖKTEM G. , YİĞİTTÜRK G., ...More

TUMOR BIOLOGY, vol.37, no.9, pp.12423-12440, 2016 (Journal Indexed in SCI) identifier identifier identifier

  • Publication Type: Article / Article
  • Volume: 37 Issue: 9
  • Publication Date: 2016
  • Doi Number: 10.1007/s13277-016-5108-9
  • Title of Journal : TUMOR BIOLOGY
  • Page Numbers: pp.12423-12440
  • Keywords: Mouse skin fibroblast cells, Mouse squamous cell lung carcinomas, Mouse embryonic stem cell, Cell cytoskeleton, Cell cycle, Cell cycle inhibitor, Flavopiridol, Heat shock protein inhibitor, Geldanamycin, SELF-RENEWAL, EXPRESSION, PLURIPOTENCY, MECHANISMS, DEATH, DIFFERENTIATION, ESTABLISHMENT, ARCHITECTURE, INHIBITION, CHAPERONES

Abstract

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.