The Putative S1PR1 Modulator ACT-209905 Impairs Growth and Migration of Glioblastoma Cells In Vitro

Overview

Journal Cancers (Basel)

Publisher MDPI

Specialty Oncology

Date 2023 Sep 9

PMID 37686550

Authors

Sandra Bien-Moller

Fan Chen

Yong Xiao

Hanjo Koppe

Gabriele Jedlitschky

Ulrike Meyer

Celine Tolksdorf

Markus Grube

Sascha Marx

Mladen V Tzvetkov

Henry W S Schroeder

Bernhard H Rauch

Affiliations

Soon will be listed here.

Abstract

Glioblastoma (GBM) is still a deadly tumor due to its highly infiltrative growth behavior and its resistance to therapy. Evidence is accumulating that sphingosine-1-phosphate (S1P) acts as an important tumor-promoting molecule that is involved in the activation of the S1P receptor subtype 1 (S1PR1). Therefore, we investigated the effect of ACT-209905 (a putative S1PR1 modulator) on the growth of human (primary cells, LN-18) and murine (GL261) GBM cells. The viability and migration of GBM cells were both reduced by ACT-209905. Furthermore, co-culture with monocytic THP-1 cells or conditioned medium enhanced the viability and migration of GBM cells, suggesting that THP-1 cells secrete factors which stimulate GBM cell growth. ACT-209905 inhibited the THP-1-induced enhancement of GBM cell growth and migration. Immunoblot analyses showed that ACT-209905 reduced the activation of growth-promoting kinases (p38, AKT1 and ERK1/2), whereas THP-1 cells and conditioned medium caused an activation of these kinases. In addition, ACT-209905 diminished the surface expression of pro-migratory molecules and reduced CD62P-positive GBM cells. In contrast, THP-1 cells increased the ICAM-1 and P-Selectin content of GBM cells which was reversed by ACT-209905. In conclusion, our study suggests the role of S1PR1 signaling in the growth of GBM cells and gives a partial explanation for the pro-tumorigenic effects that macrophages might have on GBM cells.

Citing Articles

Sphingolipid Signaling and Complement Activation in Glioblastoma: A Promising Avenue for Therapeutic Intervention.

Janneh A Biochem (Basel). 2024; 4(2):126-143.

PMID: 38894892 PMC: 11185840. DOI: 10.3390/biochem4020007.

Evaluation of Temozolomide and Fingolimod Treatments in Glioblastoma Preclinical Models.

Davy M, Genest L, Legrand C, Pelouin O, Froget G, Castagne V Cancers (Basel). 2023; 15(18).

PMID: 37760448 PMC: 10527257. DOI: 10.3390/cancers15184478.

References

Komohara Y, Ohnishi K, Kuratsu J, Takeya M . Possible involvement of the M2 anti-inflammatory macrophage phenotype in growth of human gliomas. J Pathol. 2008; 216(1):15-24. DOI: 10.1002/path.2370. View

Thakkar J, Dolecek T, Horbinski C, Ostrom Q, Lightner D, Barnholtz-Sloan J . Epidemiologic and molecular prognostic review of glioblastoma. Cancer Epidemiol Biomarkers Prev. 2014; 23(10):1985-96. PMC: 4185005. DOI: 10.1158/1055-9965.EPI-14-0275. View

DAmbrosio D, Freedman M, Prinz J . Ponesimod, a selective S1P1 receptor modulator: a potential treatment for multiple sclerosis and other immune-mediated diseases. Ther Adv Chronic Dis. 2016; 7(1):18-33. PMC: 4707431. DOI: 10.1177/2040622315617354. View

Takuwa Y, Okamoto Y, Yoshioka K, Takuwa N . Sphingosine-1-phosphate signaling in physiology and diseases. Biofactors. 2012; 38(5):329-37. DOI: 10.1002/biof.1030. View

Weichand B, Popp R, Dziumbla S, Mora J, Strack E, Elwakeel E . S1PR1 on tumor-associated macrophages promotes lymphangiogenesis and metastasis via NLRP3/IL-1β. J Exp Med. 2017; 214(9):2695-2713. PMC: 5584110. DOI: 10.1084/jem.20160392. View

Park S, Lee K, Kang S, Lee J, Sato K, Young Chung H . Sphingosine 1-phosphate induced anti-atherogenic and atheroprotective M2 macrophage polarization through IL-4. Cell Signal. 2014; 26(10):2249-58. DOI: 10.1016/j.cellsig.2014.07.009. View

Rosen H, Goetzl E . Sphingosine 1-phosphate and its receptors: an autocrine and paracrine network. Nat Rev Immunol. 2005; 5(7):560-70. DOI: 10.1038/nri1650. View

Marx S, Wilken F, Wagner I, Marx M, Troschke-Meurer S, Zumpe M . GD2 targeting by dinutuximab beta is a promising immunotherapeutic approach against malignant glioma. J Neurooncol. 2020; 147(3):577-585. DOI: 10.1007/s11060-020-03470-3. View

Lisi L, Ciotti G, Braun D, Kalinin S, Curro D, Dello Russo C . Expression of iNOS, CD163 and ARG-1 taken as M1 and M2 markers of microglial polarization in human glioblastoma and the surrounding normal parenchyma. Neurosci Lett. 2017; 645:106-112. DOI: 10.1016/j.neulet.2017.02.076. View

10.

Kolodziej M, Al Barim B, Nagl J, Weigand M, Uhl E, Uhle F . Sphingosine‑1‑phosphate analogue FTY720 exhibits a potent anti‑proliferative effect on glioblastoma cells. Int J Oncol. 2020; 57(4):1039-1046. DOI: 10.3892/ijo.2020.5114. View

11.

Liu Z, Kuang W, Zhou Q, Zhang Y . TGF-β1 secreted by M2 phenotype macrophages enhances the stemness and migration of glioma cells via the SMAD2/3 signalling pathway. Int J Mol Med. 2018; 42(6):3395-3403. PMC: 6202079. DOI: 10.3892/ijmm.2018.3923. View

12.

Ferber S, Tiram G, Sousa-Herves A, Eldar-Boock A, Krivitsky A, Scomparin A . Co-targeting the tumor endothelium and P-selectin-expressing glioblastoma cells leads to a remarkable therapeutic outcome. Elife. 2017; 6. PMC: 5644959. DOI: 10.7554/eLife.25281. View

13.

Hawkins C, Ali T, Ramanadham S, Hjelmeland A . Sphingolipid Metabolism in Glioblastoma and Metastatic Brain Tumors: A Review of Sphingomyelinases and Sphingosine-1-Phosphate. Biomolecules. 2020; 10(10). PMC: 7598277. DOI: 10.3390/biom10101357. View

14.

Alvarez S, Milstien S, Spiegel S . Autocrine and paracrine roles of sphingosine-1-phosphate. Trends Endocrinol Metab. 2007; 18(8):300-7. DOI: 10.1016/j.tem.2007.07.005. View

15.

Takuwa N, Du W, Kaneko E, Okamoto Y, Yoshioka K, Takuwa Y . Tumor-suppressive sphingosine-1-phosphate receptor-2 counteracting tumor-promoting sphingosine-1-phosphate receptor-1 and sphingosine kinase 1 - Jekyll Hidden behind Hyde. Am J Cancer Res. 2011; 1(4):460-81. PMC: 3186046. View

16.

Jo E, Sanna M, Gonzalez-Cabrera P, Thangada S, Tigyi G, Osborne D . S1P1-selective in vivo-active agonists from high-throughput screening: off-the-shelf chemical probes of receptor interactions, signaling, and fate. Chem Biol. 2005; 12(6):703-15. DOI: 10.1016/j.chembiol.2005.04.019. View

17.

Bolli M, Abele S, Binkert C, Bravo R, Buchmann S, Bur D . 2-imino-thiazolidin-4-one derivatives as potent, orally active S1P1 receptor agonists. J Med Chem. 2010; 53(10):4198-211. DOI: 10.1021/jm100181s. View

18.

Spiegel S, Milstien S . The outs and the ins of sphingosine-1-phosphate in immunity. Nat Rev Immunol. 2011; 11(6):403-15. PMC: 3368251. DOI: 10.1038/nri2974. View

19.

Genin M, Clement F, Fattaccioli A, Raes M, Michiels C . M1 and M2 macrophages derived from THP-1 cells differentially modulate the response of cancer cells to etoposide. BMC Cancer. 2015; 15:577. PMC: 4545815. DOI: 10.1186/s12885-015-1546-9. View

20.

Kapitonov D, Allegood J, Mitchell C, Hait N, Almenara J, Adams J . Targeting sphingosine kinase 1 inhibits Akt signaling, induces apoptosis, and suppresses growth of human glioblastoma cells and xenografts. Cancer Res. 2009; 69(17):6915-23. PMC: 2752891. DOI: 10.1158/0008-5472.CAN-09-0664. View