Regulation of gliomagenesis and stemness through acid sensor ASIC1a

King,Pendelton; Wan,Jingwei; Guo,Alyssa Aihui; Guo,Shanchun; Jiang,Yugang; Liu,Mingli

doi:10.3892/ijo.2021.5262

Regulation of gliomagenesis and stemness through acid sensor ASIC1a

Authors:
- Pendelton King
- Jingwei Wan
- Alyssa Aihui Guo
- Shanchun Guo
- Yugang Jiang
- Mingli Liu
View Affiliations

Affiliations: Department of Microbiology, Biochemistry and Immunology, Morehouse School of Medicine, Atlanta, GA 30310, USA, Department of Biomedical Sciences, School of Medicine Greenville, University of South Carolina, Greenville, SC 29605, USA, Department of Chemistry, Xavier University, New Orleans, LA 70125, USA, Department of Neurosurgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China
Published online on: September 10, 2021 https://doi.org/10.3892/ijo.2021.5262
Article Number: 82
Copyright: © King et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Glioblastoma multiforme (GBM) is the most prevalent and aggressive type of adult gliomas. Despite intensive therapy including surgery, radiation, and chemotherapy, invariable tumor recurrence occurs, which suggests that glioblastoma stem cells (GSCs) render these tumors persistent. Recently, the induction of GSC differentiation has emerged as an alternative method to treat GBM, and most of the current studies aim to convert GSCs to neurons by a combination of transcriptional factors. As the tumor microenvironment is typically acidic due to increased glycolysis and consequently leads to an increased production of lactic acid in tumor cells, in the present study, the role of acid‑sensing ion channel 1a (ASIC1a), an acid sensor, was explored as a tumor suppressor in gliomagenesis and stemness. The bioinformatics data from The Cancer Genome Atlas revealed that ASIC1 expression levels in GBM tumor tissues were lower than those in normal brain, and glioma patients with high ASIC1 expression had longer survival than those with low ASIC1 expression. Our immunohistochemistry data from tissue microarray revealed that ASIC1a expression was negatively associated with glioma grading. Functional studies revealed that the downregulation of ASIC1a promoted glioma cell proliferation and invasion, while upregulation of ASIC1a inhibited their proliferation and invasion. Furthermore, ASIC1a suppressed growth and proliferation of glioma cells through G1/S arrest and apoptosis induction. Mechanistically, ASIC1a negatively modulated glioma stemness via inhibition of the Notch signaling pathway and GSC markers CD133 and aldehyde dehydrogenase 1. ASIC1a is a tumor suppressor in gliomagenesis and stemness and may serve as a promising prognostic biomarker and target for GBM patients.

View Figures

View References

1	Louis DN, Perry A, Reifenberger G, von Deimling A, Figarella- Branger D, Cavenee WK, Ohgaki H, Wiestler OD, Kleihues P and Ellison DW: The 2016 World Health Organization classification of tumors of the central nervous system: A summary. Acta Neuropathol. 131:803–820. 2016. View Article : Google Scholar
2	Damaghi M, Wojtkowiak JW and Gillies RJ: pH sensing and regulation in cancer. Front Physiol. 4:3702013. View Article : Google Scholar
3	Lee WY, Huang SC, Hsu KF, Tzeng CC and Shen WL: Roles for hypoxia-regulated genes during cervical carcinogenesis: Somatic evolution during the hypoxia-glycolysis-acidosis sequence. Gynecol Oncol. 108:377–384. 2008. View Article : Google Scholar
4	Ward G, Meehan J, Gray ME, Murray AF, Argyle DJ, Kunkler IH and Langdon SP: The impact of tumor pH on cancer progression: Strategies for clinical intervention. Explor Target Antitumor Ther. 1:71–100. 2020. View Article : Google Scholar
5	Xiong ZG, Chu XP and Simon RP: Acid sensing ion channels-novel therapeutic targets for ischemic brain injury. Front Biosci. 12:1376–1386. 2007. View Article : Google Scholar
6	Berdiev BK, Xia J, McLean LA, Markert JM, Gillespie GY, Mapstone TB, Naren AP, Jovov B, Bubien JK, Ji HL, et al: Acid-sensing ion channels in malignant gliomas. J Biol Chem. 278:15023–15034. 2003. View Article : Google Scholar
7	Kapoor N, Bartoszewski R, Qadri YJ, Bebok Z, Bubien JK, Fuller CM and Benos DJ: Knockdown of ASIC1 and epithelial sodium channel subunits inhibits glioblastoma whole cell current and cell migration. J Biol Chem. 284:24526–24541. 2009. View Article : Google Scholar
8	Kapoor N, Lee W, Clark E, Bartoszewski R, McNicholas CM, Latham CB, Bebok Z, Parpura V, Fuller CM, Palmer CA and Benos DJ: Interaction of ASIC1 and ENaC subunits in human glioma cells and rat astrocytes. Am J Physiol Cell Physiol. 300:C1246–C1259. 2011. View Article : Google Scholar
9	Rooj AK, Liu Z, McNicholas CM and Fuller CM: Physical and functional interactions between a glioma cation channel and integrin-β1 require α-actinin. Am J Physiol Cell Physiol. 309:C308–C319. 2015. View Article : Google Scholar
10	Rooj AK, McNicholas CM, Bartoszewski R, Bebok Z, Benos DJ and Fuller CM: Glioma-specific cation conductance regulates migration and cell cycle progression. J Biol Chem. 287:4053–4065. 2012. View Article : Google Scholar
11	Tian Y, Bresenitz P, Reska A, El Moussaoui L, Beier CP and Gründer S: Glioblastoma cancer stem cell lines express functional acid sensing ion channels ASIC1a and ASIC3. Sci Rep. 7:136742017. View Article : Google Scholar
12	Carén H, Stricker SH, Bulstrode H, Gagrica S, Johnstone E, Bartlett TE, Feber A, Wilson G, Teschendorff AE, Bertone P, et al: Glioblastoma stem cells respond to differentiation cues but fail to undergo commitment and terminal cell-cycle arrest. Stem Cell Reports. 5:829–842. 2015. View Article : Google Scholar
13	Park NI, Guilhamon P, Desai K, McAdam RF, Langille E, O'Connor M, Lan X, Whetstone H, Coutinho FJ, Vanner RJ, et al: ASCL1 reorganizes chromatin to direct neuronal fate and suppress tumorigenicity of glioblastoma stem cells. Cell Stem Cell. 21:209–224.e7. 2017. View Article : Google Scholar
14	Lopes C, Madureira TV, Gonçalves JF and Rocha E: Disruption of classical estrogenic targets in brown trout primary hepatocytes by the model androgens testosterone and dihydrotestosterone. Aquat Toxicol. 227:1055862020. View Article : Google Scholar
15	Liu M, Inoue K, Leng T, Zhou A, Guo S and Xiong ZG: ASIC1 promotes differentiation of neuroblastoma by negatively regulating Notch signaling pathway. Oncotarget. 8:8283–8293. 2017. View Article : Google Scholar
16	Larco DO, Semsarzadeh NN, Cho-Clark M, Mani SK and Wu TJ: β-Arrestin 2 is a mediator of GnRH-(1-5) signaling in immortalized GnRH neurons. Endocrinology. 154:4726–4736. 2013. View Article : Google Scholar
17	Liu M, Inoue K, Leng T, Guo S and Xiong ZG: TRPM7 channels regulate glioma stem cell through STAT3 and Notch signaling pathways. Cell Signal. 26:2773–2781. 2014. View Article : Google Scholar
18	Salinas M, Rash LD, Baron A, Lambeau G, Escoubas P and Lazdunski M: The receptor site of the spider toxin PcTx1 on the proton-gated cation channel ASIC1a. J Physiol. 570:339–354. 2006. View Article : Google Scholar
19	Sherwood TW, Lee KG, Gormley MG and Askwith CC: Heteromeric acid-sensing ion channels (ASICs) composed of ASIC2b and ASIC1a display novel channel properties and contribute to acidosis-induced neuronal death. J Neurosci. 31:9723–9734. 2011. View Article : Google Scholar
20	Wan J, Guo AA, King P, Guo S, Saafir T, Jiang Y and Liu M: TRPM7 induces tumorigenesis and stemness through notch activation in glioma. Front Pharmacol. 11:5907232020. View Article : Google Scholar
21	Omoruyi SI, Ekpo OE, Semenya DM, Jardine A and Prince S: Exploitation of a novel phenothiazine derivative for its anti-cancer activities in malignant glioblastoma. Apoptosis. 25:261–274. 2020. View Article : Google Scholar
22	Hiyama H, Iavarone A, LaBaer J and Reeves SA: Regulated ectopic expression of cyclin D1 induces transcriptional activation of the cdk inhibitor p21 gene without altering cell cycle progression. Oncogene. 14:2533–2542. 1997. View Article : Google Scholar
23	Hitoshi S, Alexson T, Tropepe V, Donoviel D, Elia AJ, Nye JS, Conlon RA, Mak TW, Bernstein A and van der Kooy D: Notch pathway molecules are essential for the maintenance, but not the generation, of mammalian neural stem cells. Genes Dev. 16:846–858. 2002. View Article : Google Scholar
24	Purow BW, Haque RM, Noel MW, Su Q, Burdick MJ, Lee J, Sundaresan T, Pastorino S, Park JK, Mikolaenko I, et al: Expression of notch-1 and its ligands, delta-like-1 and jagged-1, is critical for glioma cell survival and proliferation. Cancer Res. 65:2353–2363. 2005. View Article : Google Scholar
25	Ishii N, Maier D, Merlo A, Tada M, Sawamura Y, Diserens AC and Van Meir EG: Frequent co-alterations of TP53, p16/CDKN2A, p14ARF, PTEN tumor suppressor genes in human glioma cell lines. Brain Pathol. 9:469–479. 1999. View Article : Google Scholar
26	Ke LD, Shi YX, Im SA, Chen X and Yung WK: The relevance of cell proliferation, vascular endothelial growth factor, and basic fibroblast growth factor production to angiogenesis and tumorigenicity in human glioma cell lines. Clin Cancer Res. 6:2562–2572. 2000.
27	Ettaiche M, Guy N, Hofman P, Lazdunski M and Waldmann R: Acid-sensing ion channel 2 is important for retinal function and protects against light-induced retinal degeneration. J Neurosci. 24:1005–1012. 2004. View Article : Google Scholar
28	Krishtal O: The ASICs: Signaling molecules? Modulators? Trends Neurosci. 26:477–483. 2003. View Article : Google Scholar
29	Wemmie JA, Price MP and Welsh MJ: Acid-sensing ion channels: Advances, questions and therapeutic opportunities. Trends Neurosci. 29:578–586. 2006. View Article : Google Scholar
30	Brockway LM, Zhou ZH, Bubien JK, Jovov B, Benos DJ and Keyser KT: Rabbit retinal neurons and glia express a variety of ENaC/DEG subunits. Am J Physiol Cell Physiol. 283:C126–C134. 2002. View Article : Google Scholar
31	Lingueglia E: Acid-sensing ion channels in sensory perception. J Biol Chem. 282:17325–17329. 2007. View Article : Google Scholar
32	Jahr H, van Driel M, van Osch GJ, Weinans H and van Leeuwen JP: Identification of acid-sensing ion channels in bone. Biochem Biophys Res Commun. 337:349–354. 2005. View Article : Google Scholar
33	Grunder S, Geissler HS, Bässler EL and Ruppersberg JP: A new member of acid-sensing ion channels from pituitary gland. Neuroreport. 11:1607–1611. 2000. View Article : Google Scholar
34	Ishibashi K and Marumo F: Molecular cloning of a DEG/ENaC sodium channel cDNA from human testis. Biochem Biophys Res Commun. 245:589–593. 1998. View Article : Google Scholar
35	Huang Y, Jiang N, Li J, Ji YH, Xiong ZG and Zha XM: Two aspects of ASIC function: Synaptic plasticity and neuronal injury. Neuropharmacology. 94:42–48. 2015. View Article : Google Scholar
36	Arun T, Tomassini V, Sbardella E, de Ruiter MB, Matthews L, Leite MI, Gelineau-Morel R, Cavey A, Vergo S, Craner M, et al: Targeting ASIC1 in primary progressive multiple sclerosis: Evidence of neuroprotection with amiloride. Brain. 136:106–115. 2013. View Article : Google Scholar
37	Yin T, Lindley TE, Albert GW, Ahmed R, Schmeiser PB, Grady MS, Howard MA and Welsh MJ: Loss of acid sensing ion channel-1a and bicarbonate administration attenuate the severity of traumatic brain injury. PLoS One. 8:e723792013. View Article : Google Scholar
38	Chu XP and Xiong ZG: Physiological and pathological functions of acid-sensing ion channels in the central nervous system. Curr Drug Targets. 13:263–271. 2012. View Article : Google Scholar
39	Pilon-Thomas S, Kodumudi KN, El-Kenawi AE, Russell S, Weber AM, Luddy K, Damaghi M, Wojtkowiak JW, Mulé JJ, Ibrahim-Hashim A and Gillies RJ: Neutralization of tumor acidity improves antitumor responses to immunotherapy. Cancer Res. 76:1381–1390. 2016. View Article : Google Scholar
40	Hjelmeland AB, Wu Q, Heddleston JM, Choudhary GS, MacSwords J, Lathia JD, McLendon R, Lindner D, Sloan A and Rich JN: Acidic stress promotes a glioma stem cell phenotype. Cell Death Differ. 18:829–840. 2011. View Article : Google Scholar
41	Arcangeli A, Pillozzi S and Becchetti A: Targeting ion channels in leukemias: A new challenge for treatment. Curr Med Chem. 19:683–696. 2012. View Article : Google Scholar
42	Lehen'kyi V, Shapovalov G, Skryma R and Prevarskaya N: Ion channnels and transporters in cancer. 5. Ion channels in control of cancer and cell apoptosis. Am J Physiol Cell Physiol. 301:C1281–C1289. 2011. View Article : Google Scholar
43	Li M and Xiong ZG: Ion channels as targets for cancer therapy. Int J Physiol Pathophysiol Pharmacol. 3:156–166. 2011.
44	Bubien JK, Keeton DA, Fuller CM, Gillespie GY, Reddy AT, Mapstone TB and Benos DJ: Malignant human gliomas express an amiloride-sensitive Na⁺ conductance. Am J Physiol. 276:C1405–C1410. 1999. View Article : Google Scholar
45	Olsen ML, Schade S, Lyons SA, Amaral MD and Sontheimer H: Expression of voltage-gated chloride channels in human glioma cells. J Neurosci. 23:5572–5582. 2003. View Article : Google Scholar
46	Kellenberger S and Schild L: International union of basic and clinical pharmacology. XCI. Structure, function, and pharmacology of acid-sensing ion channels and the epithelial Na⁺ channel. Pharmacol Rev. 67:1–35. 2015. View Article : Google Scholar
47	Wemmie JA, Taugher RJ and Kreple CJ: Acid-sensing ion channels in pain and disease. Nat Rev Neurosci. 14:461–471. 2013. View Article : Google Scholar
48	Jasti J, Furukawa H, Gonzales EB and Gouaux E: Structure of acid-sensing ion channel 1 at 1.9 a resolution and low pH. Nature. 449:316–323. 2007. View Article : Google Scholar
49	Sherwood TW and Askwith CC: Endogenous arginine-phenylalanine-amide-related peptides alter steady-state desensitization of ASIC1a. J Biol Chem. 283:1818–1830. 2008. View Article : Google Scholar
50	Sherwood TW, Frey EN and Askwith CC: Structure and activity of the acid-sensing ion channels. Am J Physiol Cell Physiol. 303:C699–C710. 2012. View Article : Google Scholar
51	Sun X, Zhao D, Li YL, Sun Y, Lei XH, Zhang JN, Wu MM, Li RY, Zhao ZF, Zhang ZR and Jiang CL: Regulation of ASIC1 by Ca²⁺/calmodulin-dependent protein kinase II in human glioblastoma multiforme. Oncol Rep. 30:2852–2858. 2013. View Article : Google Scholar
52	Vila-Carriles WH, Kovacs GG, Jovov B, Zhou ZH, Pahwa AK, Colby G, Esimai O, Gillespie GY, Mapstone TB, Markert JM, et al: Surface expression of ASIC2 inhibits the amiloride-sensitive current and migration of glioma cells. J Biol Chem. 281:19220–19232. 2006. View Article : Google Scholar
53	Clark EB, Jovov B, Rooj AK, Fuller CM and Benos DJ: Proteolytic cleavage of human acid-sensing ion channel 1 by the serine protease matriptase. J Biol Chem. 285:27130–27143. 2010. View Article : Google Scholar
54	Zhang XH, Šarić T, Mehrjardi NZ, Hamad S and Morad M: Acid-sensitive ion channels are expressed in human induced pluripotent stem cell-derived cardiomyocytes. Stem Cells Dev. 28:920–932. 2019. View Article : Google Scholar
55	Haley EM, Tilson SG, Triantafillu UL, Magrath JW and Kim Y: Acidic pH with coordinated reduction of basic fibroblast growth factor maintains the glioblastoma stem cell-like phenotype in vitro. J Biosci Bioeng. 123:634–641. 2017. View Article : Google Scholar