Abstract
Glioblastoma multiforme (GBM) is the commonest primary brain malignancy with extremely poor prognosis. Resveratrol posseses anti-cancer effects, while GBM cells respond differently to it due to certain unknown reason(s). Because the tumor-derived exosomes are supposed to influence chemosensitivity, the exosomic proteins released from resveratrol-sensitive U251 and resveratrol-resistant glioblastoma LN428 cells are profiled before (N/Exo) and after drug treatment (Res/Exo) by label-free liquid chromatography-mass spectrometry (LC-MS). The therapeutic implications of the proteomic findings are estimated by gene ontology enrichment analysis (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG)-based bioinformatic analyses and further elucidated by exosome co-incubating. The results reveal that U251/N/Exo but not U251/Res/Exo enhances resveratrol sensitivity of resveratrol-resistant LN428 cells. The resveratrol sensitive properties of U251 cells are not altered by either LN428/N/Exo or LN428/Res/Exo. U251/N/Exo contains higher levels of chromatin silencing and epidermis development proteins, while U251/Res/Exo has more oxygen transport and G protein-coupled receptor. Both of LN428/N/Exo and LN428/Res/Exo are rich in the proteins related with nucleosome assembly, microtubule-based process and chromatin silencing. In conclusion, U251/N/Exo sensitizes LN428 cells to resveratrol via delivering drug sensitizing signals, suggesting the presence of additional factor(s) that may determine the resveratrol sensitivities of glioblastoma cells.
Highlights
Glioblastoma multiform (GBM) is the most common primary brain malignancy with annual incidence of about 3/100,000 [1]
In the case of human glioblastoma cell lines, resveratrol efficiently inhibits the growth of U251 cells that are partially sensitive to TMZ and acquire TMZ resistance after a long-term treatment [30]
These results suggest that the treatment of human glioblastomas with resveratrol should be conducted in a personalized manner
Summary
Glioblastoma multiform (GBM) is the most common primary brain malignancy with annual incidence of about 3/100,000 [1]. The anti-glioblastoma drugs currently used cause severe toxic effects [4] and reduce the quality of life of GBM patients [5]. It would be of therapeutic value to explore alternative approaches for the better treatment of this lethal malignancy. Resveratrol (trans-3,5,40 -trihydroxystibene, C14 H12 O3 ), the natural plant-derived compound, posses multiple anticancer activities including sensitization of radiation and chemotherapy by promoting the differentiation of cancer cells [6] This lipophilic compound is able to cross the blood-brain barrier through simple diffusion and exerts anti-cancer effects in the brain [7].
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