| Autor: |
Sokolov DK; Institute of Molecular Biology and Biophysics, Federal Research Center of Fundamental and Translational Medicine, Novosibirsk 630117, Russia., Shevelev OB; Institute of Cytology and Genetics, Novosibirsk 630090, Russia., Khotskina AS; Institute of Cytology and Genetics, Novosibirsk 630090, Russia., Tsidulko AY; Institute of Molecular Biology and Biophysics, Federal Research Center of Fundamental and Translational Medicine, Novosibirsk 630117, Russia., Strokotova AV; Institute of Molecular Biology and Biophysics, Federal Research Center of Fundamental and Translational Medicine, Novosibirsk 630117, Russia., Kazanskaya GM; Institute of Molecular Biology and Biophysics, Federal Research Center of Fundamental and Translational Medicine, Novosibirsk 630117, Russia., Volkov AM; E.N. Meshalkin National Medical Research Center, Novosibirsk 630055, Russia., Kliver EE; E.N. Meshalkin National Medical Research Center, Novosibirsk 630055, Russia., Aidagulova SV; Institute of Molecular Biology and Biophysics, Federal Research Center of Fundamental and Translational Medicine, Novosibirsk 630117, Russia.; Laboratory of Cell Biology, Novosibirsk State Medical University, Novosibirsk 630091, Russia., Zavjalov EL; Institute of Cytology and Genetics, Novosibirsk 630090, Russia., Grigorieva EV; Institute of Molecular Biology and Biophysics, Federal Research Center of Fundamental and Translational Medicine, Novosibirsk 630117, Russia. |
| Abstrakt: |
Glioblastoma (GB) is an aggressive cancer with a high probability of recurrence, despite active chemoradiotherapy with temozolomide (TMZ) and dexamethasone (DXM). These systemic drugs affect the glycosylated components of brain tissue involved in GB development; however, their effects on heparan sulfate (HS) remain unknown. Here, we used an animal model of GB relapse in which SCID mice first received TMZ and/or DXM (simulating postoperative treatment) with a subsequent inoculation of U87 human GB cells. Control, peritumor and U87 xenograft tissues were investigated for HS content, HS biosynthetic system and glucocorticoid receptor (GR, Nr3c1 ). In normal and peritumor brain tissues, TMZ/DXM administration decreased HS content (5-6-fold) but did not affect HS biosynthetic system or GR expression. However, the xenograft GB tumors grown in the pre-treated animals demonstrated a number of molecular changes, despite the fact that they were not directly exposed to TMZ/DXM. The tumors from DXM pre-treated animals possessed decreased HS content (1.5-2-fold), the inhibition of HS biosynthetic system mainly due to the -3-3.5-fold down-regulation of N-deacetylase/N-sulfotransferases ( Ndst1 and Ndst2 ) and sulfatase 2 ( Sulf2 ) expression and a tendency toward a decreased expression of the GRalpha but not the GRbeta isoform. The GRalpha expression levels in tumors from DXM or TMZ pre-treated mice were positively correlated with the expression of a number of HS biosynthesis-involved genes ( Ext1/2 , Ndst1/2 , Glce , Hs2st1 , Hs6st1/2 ), unlike tumors that have grown in intact SCID mice. The obtained data show that DXM affects HS content in mouse brain tissues, and GB xenografts grown in DXM pre-treated animals demonstrate attenuated HS biosynthesis and decreased HS content. |
