Presenilin1 Exerts Antiproliferative Effects by Repressing the Wnt/β-catenin Pathway in Glioblastoma

Overview

Journal Cell Commun Signal

Publisher Biomed Central

Specialties Biochemistry
Cell Biology

Date 2020 Feb 13

PMID 32046730

Citations 8

Authors

Wei Yang

Peng-Fei Wu

Jian-Xing Ma

Mao-Jun Liao

Lun-Shan Xu

Min-Hui Xu

Liang Yi

Affiliations

Soon will be listed here.

Abstract

Background: Glioblastoma and Alzheimer's disease (AD) are the most common and devastating diseases in the central nervous system. The dysfunction of Presenilin1 is the main reason for AD pathogenesis. However, the molecular function of Presenilin1 and its relative mechanism in glioblastoma remain unclear.

Methods: Expression of presenilin1 in glioma was determined by IHC. CCK-8, colony formation, Flow cytometry, Edu staining were utilized to evaluate functions of presenilin1 on glioblastoma proliferation. The mechanism of above process was assessed by Western blotting and cell immunofluorescence. Mouse transplanting glioblastoma model and micro-MRI detection were used to verified presenilin1 function in vivo.

Results: In this study, we found that all grades of glioma maintained relatively low Presenilin1 expression and that the expression of Presenilin1 in high-grade glioma was significantly lower than that in low-grade glioma. Moreover, the Presenilin1 level had a positive correlation with glioma and glioblastoma patient prognosis. Next, we determined that Presenilin1 inhibited the growth and proliferation of glioblastoma cells by downregulating CDK6, C-myc and Cyclin D1 to arrest the cell cycle at the G1/S phase. Mechanistically, Presenilin1 promoted the direct phosphorylation of β-catenin at the 45 site and indirect phosphorylation at the 33/37/41 site, then decreased the stabilized part of β-catenin and hindered its translocation from the cytoplasm to the nucleus. Furthermore, we found that Presenilin1 downregulation clearly accelerated the growth of subcutaneous glioblastoma, and Presenilin1 overexpression significantly repressed the subcutaneous and intracranial transplantation of glioblastoma by hindering β-catenin-dependent cell proliferation.

Conclusion: Our data implicate the antiproliferative effect of Presenilin1 in glioblastoma by suppressing Wnt/β-catenin signaling, which may provide a novel therapeutic agent for glioblastoma. Video Abstract.

Citing Articles

MicroRNAs: pioneering regulators in Alzheimer's disease pathogenesis, diagnosis, and therapy.

Li Y, Fu Q, Guo M, Du Y, Chen Y, Cheng Y Transl Psychiatry. 2024; 14(1):367.

PMID: 39256358 PMC: 11387755. DOI: 10.1038/s41398-024-03075-8.

Yttrium oxide nanoparticles ameliorates calcium hydroxide and calcium titanate nanoparticles induced genomic DNA and mitochondrial damage, ROS generation and inflammation.

Mohamed H, Farouk A, Elbasiouni S, Nasif K, Safwat G Sci Rep. 2024; 14(1):13015.

PMID: 38844752 PMC: 11156978. DOI: 10.1038/s41598-024-62877-4.

Muscle Psn gene combined with exercise contribute to healthy aging of skeletal muscle and lifespan by adaptively regulating Sirt1/PGC-1α and arm pathway.

Gao Y, Wen D, Du Z, Wang J, Wang S PLoS One. 2024; 19(5):e0300787.

PMID: 38753634 PMC: 11098322. DOI: 10.1371/journal.pone.0300787.

The critical role of γ-secretase and its inhibitors in cancer and cancer therapeutics.

Song C, Zhang J, Xu C, Gao M, Li N, Geng Q Int J Biol Sci. 2023; 19(16):5089-5103.

PMID: 37928268 PMC: 10620818. DOI: 10.7150/ijbs.87334.

Presenilin-1 (PSEN1) Mutations: Clinical Phenotypes beyond Alzheimer's Disease.

Yang Y, Bagyinszky E, An S Int J Mol Sci. 2023; 24(9).

PMID: 37176125 PMC: 10179041. DOI: 10.3390/ijms24098417.

References

Li P, Lin X, Zhang J, Li Y, Lu J, Huang F . The expression of presenilin 1 enhances carcinogenesis and metastasis in gastric cancer. Oncotarget. 2016; 7(9):10650-62. PMC: 4891148. DOI: 10.18632/oncotarget.7298. View

Aldape K, Brindle K, Chesler L, Chopra R, Gajjar A, Gilbert M . Challenges to curing primary brain tumours. Nat Rev Clin Oncol. 2019; 16(8):509-520. PMC: 6650350. DOI: 10.1038/s41571-019-0177-5. View

Suzuki K, Iwata A, Iwatsubo T . The past, present, and future of disease-modifying therapies for Alzheimer's disease. Proc Jpn Acad Ser B Phys Biol Sci. 2017; 93(10):757-771. PMC: 5790756. DOI: 10.2183/pjab.93.048. View

Hulleman E, Quarto M, Vernell R, Masserdotti G, Colli E, Kros J . A role for the transcription factor HEY1 in glioblastoma. J Cell Mol Med. 2008; 13(1):136-46. PMC: 3823042. DOI: 10.1111/j.1582-4934.2008.00307.x. View

Otto T, Sicinski P . Cell cycle proteins as promising targets in cancer therapy. Nat Rev Cancer. 2017; 17(2):93-115. PMC: 5345933. DOI: 10.1038/nrc.2016.138. View

Navarro V, Vincent J, Mazella J . Shedding of the luminal domain of the neurotensin receptor-3/sortilin in the HT29 cell line. Biochem Biophys Res Commun. 2002; 298(5):760-4. DOI: 10.1016/s0006-291x(02)02564-0. View

Ham S, Kim T, Ryu J, Kim Y, Tang Y, Im H . Comprehensive MicroRNAome Analysis of the Relationship Between Alzheimer Disease and Cancer in PSEN Double-Knockout Mice. Int Neurourol J. 2019; 22(4):237-245. PMC: 6312969. DOI: 10.5213/inj.1836274.137. View

Kristoffersen K, Nedergaard M, Villingshoj M, Borup R, Broholm H, Kjaer A . Inhibition of Notch signaling alters the phenotype of orthotopic tumors formed from glioblastoma multiforme neurosphere cells but does not hamper intracranial tumor growth regardless of endogene Notch pathway signature. Cancer Biol Ther. 2014; 15(7):862-77. PMC: 4100987. DOI: 10.4161/cbt.28876. View

Kang D, Soriano S, Xia X, Eberhart C, De Strooper B, Zheng H . Presenilin couples the paired phosphorylation of beta-catenin independent of axin: implications for beta-catenin activation in tumorigenesis. Cell. 2002; 110(6):751-62. DOI: 10.1016/s0092-8674(02)00970-4. View

10.

Sasmita A, Wong Y, Ling A . Biomarkers and therapeutic advances in glioblastoma multiforme. Asia Pac J Clin Oncol. 2017; 14(1):40-51. DOI: 10.1111/ajco.12756. View

11.

Xu G, Li J . CDK4, CDK6, cyclin D1, p16(INK4a) and EGFR expression in glioblastoma with a primitive neuronal component. J Neurooncol. 2017; 136(3):445-452. DOI: 10.1007/s11060-017-2674-7. View

12.

Masui K, Tanaka K, Akhavan D, Babic I, Gini B, Matsutani T . mTOR complex 2 controls glycolytic metabolism in glioblastoma through FoxO acetylation and upregulation of c-Myc. Cell Metab. 2013; 18(5):726-39. PMC: 3840163. DOI: 10.1016/j.cmet.2013.09.013. View

13.

Ostrom Q, Gittleman H, Xu J, Kromer C, Wolinsky Y, Kruchko C . CBTRUS Statistical Report: Primary Brain and Other Central Nervous System Tumors Diagnosed in the United States in 2009-2013. Neuro Oncol. 2017; 18(suppl_5):v1-v75. PMC: 8483569. DOI: 10.1093/neuonc/now207. View

14.

Lane C, Hardy J, Schott J . Alzheimer's disease. Eur J Neurol. 2017; 25(1):59-70. DOI: 10.1111/ene.13439. View

15.

Ma H, Yuan L, Li W, Xu K, Yang L . The LncRNA H19/miR-193a-3p axis modifies the radio-resistance and chemotherapeutic tolerance of hepatocellular carcinoma cells by targeting PSEN1. J Cell Biochem. 2018; 119(10):8325-8335. DOI: 10.1002/jcb.26883. View

16.

Roperch J, Alvaro V, Prieur S, Tuynder M, Nemani M, Lethrosne F . Inhibition of presenilin 1 expression is promoted by p53 and p21WAF-1 and results in apoptosis and tumor suppression. Nat Med. 1998; 4(7):835-8. DOI: 10.1038/nm0798-835. View

17.

Ji Q, Ma J, Liu R, Li X, Shen F, Huang L . CDCA7L promotes glioma proliferation by targeting CCND1 and predicts an unfavorable prognosis. Mol Med Rep. 2019; 20(2):1149-1156. PMC: 6625380. DOI: 10.3892/mmr.2019.10349. View

18.

Fortini M . Gamma-secretase-mediated proteolysis in cell-surface-receptor signalling. Nat Rev Mol Cell Biol. 2002; 3(9):673-84. DOI: 10.1038/nrm910. View

19.

Rogaev E, Sherrington R, Rogaeva E, Levesque G, Ikeda M, Liang Y . Familial Alzheimer's disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer's disease type 3 gene. Nature. 1995; 376(6543):775-8. DOI: 10.1038/376775a0. View

20.

De Strooper B, Annaert W, Cupers P, Saftig P, Craessaerts K, Mumm J . A presenilin-1-dependent gamma-secretase-like protease mediates release of Notch intracellular domain. Nature. 1999; 398(6727):518-22. DOI: 10.1038/19083. View