Stem-23. Inhibiting Protein Phosphatase 2a Increases the Antitumor Effect of Protein Arginine Methyltransferase 5 Inhibition in Models of Glioblastoma
Year: 2020
Type: conference-abstract
Abstract: BACKGROUND: Despite multi-model therapy of maximal surgical resection, radiation, chemotherapy, and tumor treating fields, median survival of Glioblastoma (GBM) patients is less than two years. Protein Arginine Methyltransferase 5 (PRMT5) catalyzes the symmetric di-methylation of arginine residues and is overexpressed in GBM. Inhibition of PRMT5 causes senescence of immature GBM tumor cells. LB100, first-in-class small molecule 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 the 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 mice 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.
Source: Neuro-Oncology
Authors: Yeshavanth Kumar Banasavadi Siddegowda, Hannah Sur, Yoshihiro Otani, Guruprasad Rachaiah, Sriya Namagiri, Ashis Chowdhury, Cole Lewis, Toshihiko Shimizu, Arunakumar Gangaplara, Xiang Wang, Amélie Vézina, Dragan Maric, Sadhana Jackson, Yuanqing Yan, Zhuang Zhengping, Abhik Ray-Chaudhury, Sachin Kumar, Prashant Chittiboina, John Heiss, Ji Young Yoo, Balveen Kaur
Institutions: National Institutes of Health, National Institute of Neurological Disorders and Stroke, The University of Texas Health Science Center at Houston, Karnataka Veterinary Animal and Fisheries Sciences University, National Heart, Lung, and Blood Institute, National Cancer Institute, Center for Cancer Research, Indian Institute of Technology Guwahati
Language: English
Subfield: Genetics
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W4235577248