Inhibiting protein phosphatase 2A increases the antitumor effect of protein arginine methyltransferase 5 inhibition in models of glioblastoma.

BACKGROUND: Despite multi-model therapy of maximal surgical resection, radiation, chemotherapy, and tumor-treating fields, the median survival of glioblastoma (GBM) patients is less than 15 months. Protein arginine methyltransferase 5 (PRMT5) catalyzes the symmetric dimethylation of arginine residues and is overexpressed in GBM. Inhibition of PRMT5 causes senescence in stem-like GBM tumor cells. LB100, a first-in-class small molecular inhibitor of protein phosphatase 2A (PP2A), can sensitize therapy-resistant tumor cells. Here, we tested the anti-GBM effect of concurrent PRMT5 and PP2A inhibition. METHODS: Patient-derived primary GBM neurospheres (GBMNS), transfected with PRMT5 target-specific siRNA, were treated with LB100 and subjected to in vitro assays including PP2A activity and western blot. The intracranial mouse xenograft model was used to test the in vivo antitumor efficacy of combination treatment. RESULTS: We found that PRMT5 depletion increased PP2A activity in GBMNS. LB100 treatment significantly reduced the viability of PRMT5-depleted GBMNS compared to PRMT5-intact GBMNS. LB100 enhanced G1 cell cycle arrest induced by PRMT5 depletion. Combination therapy also increased the expression of phospho-MLKL. Necrostatin-1 rescued PRMT5-depleted cells from the cytotoxic effects of LB100, indicating that necroptosis caused the enhanced cytotoxicity of combination therapy. In the in vivo mouse tumor xenograft model, LB100 treatment combined with transient depletion of PRMT5 significantly decreased tumor size and prolonged survival, while LB100 treatment alone had no survival benefit. CONCLUSION: Overall, combined PRMT5 and PP2A inhibition had significantly greater antitumor effects than PRMT5 inhibition alone.

Significance of LOH of tumor suppressor gene D8S133,D8S136,D8S137 and D17S855 in multifocal prostate cancer / 肿瘤研究与临床

Objecfive Most prostate cancer contains two or more widely separate turnors.To study the origin of prostate cancer based on the analysis of microsatellite alteration in separate tumors from the same prostate.Methods A polymerase chain reaction (PCR) was used to examine the allelic loss pattern of 4 microsatellite polymorphic markers on chromosome 8p (D8S133,D8S136,D8S137) and 17q (D17S855) in multifocal tumors of prostate from 19 patients.DNA samples were obtained from different regions of distinctly separate tumors on single case using microdissection technique.Results The overall frequence of LOH at D8S133,D8S136,D8S137 and D17S855 for all informative cases was 74%,38%,86% and 46%respectively in 40 separate tumors of prostate from 19 patients.The pattern of allelic loss was not identical in 15 of 18 (83%) informative cases. It showed that the different regions of prostate cancer were independent origin respectively.Discordant pattern of histology was observe in distantly separate regions.whereas the same allele was consistently lost in samples from different regions of the same tumor in 3 cases. Condusion Current data supports independent origin of multiple tumors in most prostate cancer patients.