Is Upregulation of Aquaporin 4-M1 Isoform Responsible for the Loss of Typical Orthogonal Arrays of Particles in Astrocytomas?

Fallier‐Becker, Petra; Nieser, Maike; Wenzel, U. D.; Ritz, Rainer; Noell, Susan

doi:10.3390/ijms17081230

Cited by 13 publications

(18 citation statements)

References 26 publications

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“…The role of AQP4 isoforms in glioblastoma biology has been addressed in earlier studies, which have shown that high-grade gliomas display higher expression of AQP4 than low-grade tumors (7). Furthermore, OAPs have been shown to be disintegrated or absent in glioblastomas, and more recently an inverse correlation between OAP prevalence and malignancy was demonstrated (8).…”

Section: Mahmood Amiry-moghaddammentioning

confidence: 99%

AQP4 and the Fate of Gliomas

Amiry-Moghaddam

2019

Cancer Research

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High-grade glioma is the most common primary brain cancer type and is characterized by invasive and fast growth. In a previous issue of Cancer Research, Simone and colleagues show that the two isoforms of the aquaporin-4 (AQP4) water channel may determine the fate of gliomas. Glioma cell lines expressing the M23-AQP4 isoform, which forms large aggregates of orthogonal arrays of particles, shrink and undergo apoptosis, whereas cell lines expressing the tetramer-forming M1-AQP4 isoform display higher activity of matrix metalloproteinases, making them more invasive. This study provides new insight on the role of AQP4 isoforms in the biology of gliomas.See related article by Simone and colleagues; Cancer Res 79(9): 2182-94.Glioma is a relatively common type of tumor in the central nervous system and comprises tumors that differ in malignancy and cellular origin. Glioblastoma multiforme (GBM) is a glioma subtype originating in astrocytes. It is the most common type of brain cancer in adults and is characterized by diffuse and invasive growth, which in combination with high frequency of recurrence make the prognosis very poor (1). Most patients die within 8-18 months of diagnosis and the 2-year survival rate is about 3%. Thus, GBM represents a significant burden on the society and novel therapies are urgently needed.The study by Simone and colleagues addresses the role of different isoforms of the water channel aquaporin-4 (AQP4) in the pathogenicity of gliomas (2). AQP4 is the predominant brain water channel protein. It is mainly expressed by astrocytes, where it is distributed in a highly polarized manner. The astrocytic foot processes abutting brain microvessels display about 10-fold higher AQP4 density than the astrocyte membrane domains facing the neuropil (3). The dystrophin-associated protein (DAP) complex is responsible for the polarized distribution of AQP4 as it connects intracellular actin cytoskeleton to extracellular matrix molecules present in the perivascular basal lamina. More specifically, the endfoot AQP4 molecules are tethered to the membrane by isoforms of syntrophin, which are PDZ domain-containing members of the DAP complex that interact with the intracellular tail of AQP4 (4).AQP4 is expressed as two major isoforms that differ in regard to methionine (M) starting codon. The shorter and more abundant form is called M23 and the longer and less abundant form is called M1. The two AQP4 isoforms form heterotetramers, which in turn aggregate into higher order structures called orthogonal arrays of particles (OAP). The two AQP4 isoforms display the same water permeability, with the main established difference between them being their ability to aggregate into OAPs. The shorter M23 isoform forms large OAPs, whereas the longer M1 isoform forms very small or no OAPs (5). The functional significance of the OAPs has not yet been established, but in vitro data indicate that the M23 isoform may function as adhesion molecules, whereas the M1 isoform is mobile in the plasma membrane and is more involved in cell ...

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Section: Mahmood Amiry-moghaddammentioning

confidence: 99%

AQP4 and the Fate of Gliomas

Amiry-Moghaddam

2019

Cancer Research

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“…An interesting study by Noell and colleagues reports none or only small OAPs on glioblastoma samples analyzed by freeze-fracture electron microscopy, indicating that redistribution of AQP4 and OAPs could be one of the earliest indicators of glioma transformation (17). Interestingly, although a correlation between the decrease in OAPs and increasing grade of malignancy of astrocytomas has been reported, this was not consistent with an upregulation of M1-AQP4 in relation to M23-AQP4 (18).…”

Section: Introductionmentioning

confidence: 96%

AQP4 Aggregation State Is a Determinant for Glioma Cell Fate

et al. 2019

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The glial water channel protein aquaporin-4 (AQP4) forms heterotetramers in the plasma membrane made of the M23-AQP4 and M1-AQP4 isoforms. The isoform ratio controls AQP4 aggregation into supramolecular structures called orthogonal arrays of particles (AQP4-OAP). The role of AQP4 aggregation into OAP in malignant gliomas is still unclear. In this study, we demonstrate that AQP4 aggregation/disaggregation into OAP influences the biology of glioma cells. Selective expression of the OAP-forming isoform M23-AQP4 (AQP4-OAP) triggered cell shape changes in glioma cells associated with alterations to the F-actin cytoskeleton that affected apoptosis. By contrast, expression of M1-AQP4 (AQP4-tetramers), which is unable to aggregate into OAP, ameliorated glioma cell invasiveness, improved cell migration, and increased methalloproteinase-9 activity. Two prolines (254 and 296) at the C-terminus tail were shown to be important in mediating the relationship between the actin cytoskeleton and AQP4-OAP and AQP4-tetramers. In conclusion, this study demonstrates that AQP4 aggregation state might be an important determinant in orienting glioma cells to persist or perish. AQP4 disaggregation may potentiate invasiveness potential, whereas AQP4 aggregation may activate the apoptotic path. This study shows a new perspective on the role of AQP4 in brain tumors not necessarily associated with edema formation but with AQP4 aggregation/disaggregation dynamics and their link with the actin cytoskeleton.Significance: This study demonstrates how AQP4 aggregation influences plasma membrane dynamics to alter cell proliferation, invasiveness, migration, and apoptotic potential in glioma cells.

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“…Interestingly, the abundance and the size of OAPs differ not only in comparison with healthy cells but also between different stages of glioblastomas. High-grade astrocytoma tumors are reported to express only a few typical OAPs, whereas low-grade astrocytomas express more OAPs; this discovery is among the important steps in unraveling of the role of OAPs in astrocytoma malignancy [52,74]. Functional rearrangements of OAPs in glioblastomas remain to be further evaluated from the perspective of rearrangements of different AQP4 isoforms, because not all AQP4 molecules in the plasma membranes of glioblastoma cells are arranged in OAPs [52,71].…”

Section: Oaps and Glioma Invasivenessmentioning

confidence: 93%

“…The expression of AQP4c (M23) directed glioma cells to apoptosis through interactions mediated by actin cytoskeleton, therefore reducing the invasive potential [69]. The protein expression of AQP4 in human glioblastoma is indeed upregulated in comparison with healthy brain tissue [52,74,75]. However, the ratio of expression between AQP4a (M1) and AQP4c (M23) appears to remain similar [52]; therefore, one has to look at additional levels that affect the incorporation of AQP4 into the plasma membrane and their interactions within OAPs.…”

Section: Oaps and Glioma Invasivenessmentioning

confidence: 99%

Insights into Cell Surface Expression, Supramolecular Organization, and Functions of Aquaporin 4 Isoforms in Astrocytes

Jorgačevski

Zorec

Potokar

2020

Cells

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Aquaporin 4 (AQP4) is the most abundant water channel in the central nervous system (CNS). Its expression is confined to non-neuronal glial cells, predominantly to astrocytes that represent a heterogeneous glial cell type in the CNS. The membrane of astrocyte processes, which align brain capillaries and pia, is particularly rich in AQP4. Several isoforms of AQP4 have been described; however, only some (AQP4a (M1), AQP4 c (M23), AQP4e, and AQP4ex) have been identified in the plasma membrane assemblies of astrocytes termed orthogonal arrays of particles (OAPs). Intracellular splicing isoforms (AQP4b, AQP4d, AQP4f, AQP4-Δ4) have been documented, and most of them are postulated to have a role in the cell surface distribution of the plasma membrane isoforms and in the formation of OAPs in murine and human astrocytes. Although OAPs have been proposed to play various roles in the functioning of astrocytes and CNS tissue as a whole, many of these still need to be described. OAPs are studied primarily from the perspective of understanding water permeability regulation through the plasma membrane and of their involvement in cell adhesion and in the dynamics of astrocytic processes. This review describes the cellular distribution of various AQP4 isoforms and their implications in OAP assembly, which is regulated by several intracellular and extracellular proteins.

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Is Upregulation of Aquaporin 4-M1 Isoform Responsible for the Loss of Typical Orthogonal Arrays of Particles in Astrocytomas?

Cited by 13 publications

References 26 publications

AQP4 and the Fate of Gliomas

AQP4 and the Fate of Gliomas

AQP4 Aggregation State Is a Determinant for Glioma Cell Fate

Insights into Cell Surface Expression, Supramolecular Organization, and Functions of Aquaporin 4 Isoforms in Astrocytes

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