Distinct sulfonation activities in resveratrol‐sensitive and resveratrol‐insensitive human glioblastoma cells

Glioblastoma multiforme (GBM) cells show different responses to resveratrol, for unknown reasons. Our data from human medulloblastoma cells and primary cultures of rat brain cells revealed an inverse correlation of sulfonation activity with resveratrol sensitivities, providing a clue to the underlying mechanisms of the variable sensitivities of GBM cells to resveratrol. In this study, we found that U251 cells were sensitive and LN229 cells were insensitive to resveratrol. Thus, these two cell lines were taken as comparable models for elucidating the influence of sulfonation activities on resveratrol sensitivity. HPLC showed identical resveratrol metabolic patterns in both cell lines. LC/MS and high‐resolution mass MS analyses further demonstrated that resveratrol monosulfate generated by sulfotransferases (SULTs) was the major metabolite of human GBM cells. The levels of brain‐associated SULT (SULT1A1, SULT1C2, and SULT4A1) expression in U251 cells were lower than those in LN229 cells, suggesting the inverse relationship of SULT‐mediated sulfonation activity with high intracellular resveratrol bioavailability and resveratrol sensitivity of human GBM cells. Furthermore, immunohistochemical staining revealed reductions in expression of the three brain‐associated SULTs in 72.8%, 47.5% and 66.3% of astrocytomas, respectively. Therefore, the levels of brain‐associated SULTs and sulfonation activity mediated by them could be important parameters for evaluating the potential response of human GBM cells to resveratrol, and may have value in the personalized treatment of GBMs with resveratrol. Database Nucleotide sequence data for SULT1A1, SULT1C2 and SULT4A1 are available in the GenBank database under the accession numbers BC110887, BC005353, and BC028171. Glioblastoma LN‐229 cells are sensitive but U251 cells are resistant to resveratrol. Although they share identical resveratrol metabolic patterns and the same metabolite (resveratrol monosulfate), the levels of brain‐associated sulfotransferases (SULTs) in U251 cells were lower than that in LN229 cells. These phenomena suggest the opposite relationship of SULT‐mediated sulfonation activity with intracellular resveratrol bioavailability and resveratrol‐sensitivity of human glioblastoma cells.