Glycogen synthase kinase-3 inhibition in glioblastoma multiforme cells induces apoptosis, cell cycle arrest and changing biomolecular structure

被引:22
作者
Acikgoz, Eda [1 ,2 ]
Guler, Gunnur [3 ]
Camlar, Mahmut [4 ]
Oktem, Gulperi [1 ]
Aktug, Huseyin [1 ]
机构
[1] Ege Univ, Fac Med, Dept Histol & Embryol, TR-35100 Izmir, Turkey
[2] Yuzuncu Yil Univ, Fac Med, Dept Histol & Embryol, TR-65080 Van, Turkey
[3] Ege Univ, Ctr Drug Res & Dev & Pharmacokinet Applicat ARGEF, TR-35100 Izmir, Turkey
[4] Saglik Bilimleri Univ, Izmir Tepecik Educ & Res Hosp, Dept Neurosurg, TR-35100 Izmir, Turkey
关键词
Glioblastoma multiforme; Glycogen synthase kinase-3; Apoptosis; Cell cycle; ATR-FTIR spectroscopy; Drug action mechanism; INFRARED-SPECTROSCOPY; FTIR SPECTROSCOPY; GLIOMA-CELLS; CANCER; EXPRESSION; SPECTRA; ACID; CLASSIFICATION; CONFORMATION; CASPASE-3;
D O I
10.1016/j.saa.2018.10.036
中图分类号
O433 [光谱学];
学科分类号
0703 ; 070302 ;
摘要
Glioblastoma multiforme (GBM) is the most malignant and aggressive primary human brain tumors. The regulatory pathways of apoptosis are altered in GBMs, leading to a survival advantage of the tumor cells. Thus, identification of target molecules, which are effective in triggering of the cell death mechanisms in GBM, is an essential strategy for therapeutic purposes. Glycogen synthase kinase-3 (GSK-3) plays an important role in apoptosis, proliferation and cell cycle. This study focused on the effect of GSK-3 inhibitor IX in the GBM cells. Apoptosis induction was determined by Annexin-V assay, multicaspase activity and immunofluorescence analyses. Concentration-dependent effects of GSK-3 inhibitor IX on the cell cycle were also evaluated. Moreover, the effect of GSK inhibitor on the cellular biomolecules was assessed by using ATR-FTIR spectroscopy. Our assay results indicated that GSK-3 inhibitor IX induces apoptosis, resulting in a significant increase in the expression of caspase-3 and caspase-8 proteins. Cell cycle analyses revealed that GSK-3 inhibitor IX leads to dose -dependent G2/M-phase cell cycle arrest. Based on the FTIR data, treatment of GBM cells causes dysregulation in the carbohydrate metabolism and induces apoptotic cell death which was characterized by the spectral alterations in nucleic acids, an increment in the lipid amount with disordering state and compositional changes in the cellular proteins. These findings suggest that GSK-3 inhibitor IX exhibits anti-cancer effects by inducing apoptosis and changing biomolecular structure of membrane lipids, carbohydrates, nucleic acids and proteins, and thus, may be further evaluated as a potential effective candidate agent for the GBM combination therapies. (C) 2018 Elsevier B.V. All rights reserved.
引用
收藏
页码:150 / 164
页数:15
相关论文
共 54 条
[1]   Caspase 8 is absent or low in many ex vivo gliomas [J].
Ashley, DM ;
Riffkin, CD ;
Muscat, AM ;
Knight, MJ ;
Kaye, AH ;
Novak, U ;
Hawkins, CJ .
CANCER, 2005, 104 (07) :1487-1496
[2]   The infrared absorption of amino acid side chains [J].
Barth, A .
PROGRESS IN BIOPHYSICS & MOLECULAR BIOLOGY, 2000, 74 (3-5) :141-173
[3]   Lipid metabolic reprogramming in cancer cells [J].
Beloribi-Djefaflia, S. ;
Vasseur, S. ;
Guillaumond, F. .
ONCOGENESIS, 2016, 5 :e189-e189
[4]   The paradoxical pro- and anti-apoptotic actions of GSK3 in the intrinsic and extrinsic apoptosis signaling pathways [J].
Beurel, Eleonore ;
Jope, Richard S. .
PROGRESS IN NEUROBIOLOGY, 2006, 79 (04) :173-189
[5]   Synchrotron based Fourier-transform infrared microspectroscopy as sensitive technique for the detection of early apoptosis in U-87 MG cells [J].
Buriankova, L. ;
Nadova, Z. ;
Jancura, D. ;
Refregiers, M. ;
Yousef, I. ;
Mikes, J. ;
Miskovsky, P. .
LASER PHYSICS LETTERS, 2010, 7 (08) :613-620
[6]   Translation inhibition during the induction of apoptosis: RNA or protein degradation? [J].
Bushell, M ;
Stoneley, M ;
Sarnow, P ;
Willis, AE .
BIOCHEMICAL SOCIETY TRANSACTIONS, 2004, 32 :606-610
[7]   Translation initiation factor modifications and the regulation of protein synthesis in apoptotic cells [J].
Clemens, MJ ;
Bushell, M ;
Jeffrey, IW ;
Pain, VM ;
Morley, SJ .
CELL DEATH AND DIFFERENTIATION, 2000, 7 (07) :603-615
[8]   The effect of anticancer drugs on seven cell lines monitored by FTIR spectroscopy [J].
Derenne, Allison ;
Verdonck, Magali ;
Goormaghtigh, Erik .
ANALYST, 2012, 137 (14) :3255-3264
[9]   Multiple Biological Activities of Lactic Acid in Cancer: Influences on Tumor Growth, Angiogenesis and Metastasis [J].
Dhup, Suveera ;
Dadhich, Rajesh Kumar ;
Porporato, Paolo Ettore ;
Sonveaux, Pierre .
CURRENT PHARMACEUTICAL DESIGN, 2012, 18 (10) :1319-1330
[10]   Infrared spectroscopy of cells and tissues: Shining light onto a novel subject [J].
Diem, M ;
Boydston-White, S ;
Chiriboga, L .
APPLIED SPECTROSCOPY, 1999, 53 (04) :148A-161A