Figure S7 from Antisecretory Factor–Mediated Inhibition of Cell Volume Dynamics Produces Antitumor Activity in Glioblastoma

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posted on 2023-04-03, 16:45 authored by Shirin Ilkhanizadeh, Hanna Sabelström, Yekaterina A. Miroshnikova, Aaron Frantz, Wen Zhu, Aurora Idilli, Jon N. Lakins, Christin Schmidt, David A. Quigley, Trenten Fenster, Edith Yuan, Jacqueline R. Trzeciak, Supna Saxena, Olle R. Lindberg, Janna K. Mouw, Jason A. Burdick, Sergey Magnitsky, Mitchel S. Berger, Joanna J. Phillips, Daniele Arosio, Dandan Sun, Valerie M. Weaver, William A. Weiss, Anders I. Persson

Fig. S7. AF reversed compression-induced transcriptional phenotype of GBM tumorspheres. Both (A-B) smaller and (C-D) larger GBM43 tumorspheres expanded in response to 48h compression. (***P < 0.05, Student's t-test). (E) Principle components analysis of all expressed genes. The first principle component is associated with GBM subtype, while the second principle component is associated with the presence of compression. (F) Heat map of genes differentially expressed when comparing compression to other conditions (see supplementary table S1 for gene list).

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ARTICLE ABSTRACT

Interstitial fluid pressure (IFP) presents a barrier to drug uptake in solid tumors, including the aggressive primary brain tumor glioblastoma (GBM). It remains unclear how fluid dynamics impacts tumor progression and can be targeted therapeutically. To address this issue, a novel telemetry-based approach was developed to measure changes in IFP during progression of GBM xenografts. Antisecretory factor (AF) is an endogenous protein that displays antisecretory effects in animals and patients. Here, endogenous induction of AF protein or exogenous administration of AF peptide reduced IFP and increased drug uptake in GBM xenografts. AF inhibited cell volume regulation of GBM cells, an effect that was phenocopied in vitro by the sodium-potassium-chloride cotransporter 1 (SLC12A2/NKCC1) inhibitor bumetanide. As a result, AF induced apoptosis and increased survival in GBM models. In vitro, the ability of AF to reduce GBM cell proliferation was phenocopied by bumetanide and NKCC1 knockdown. Next, AF's ability to sensitize GBM cells to the alkylating agent temozolomide, standard of care in GBM patients, was evaluated. Importantly, combination of AF induction and temozolomide treatment blocked regrowth in GBM xenografts. Thus, AF-mediated inhibition of cell volume regulation represents a novel strategy to increase drug uptake and improve outcome in GBM. Mol Cancer Res; 16(5); 777–90. ©2018 AACR.