Glioma-specific Cation Conductance Regulates Migration and Cell Cycle Progression

Rooj, Arun K.; McNicholas, Carmel M.; Bartoszewski, Rafał; Bebök, Zsuzsanna; Benos, Dale J.; Fuller, Catherine M.

doi:10.1074/jbc.m111.311688

Cited by 86 publications

(87 citation statements)

References 51 publications

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“…Cell proliferation and migration assays carried out in these studies demonstrated that the translocation of ASIC2 to the plasma membrane inhibited the proliferation and mobility of GBM cells (396,397). The observation that PcTx1 was a highly potent inhibitor of this conductance, and inhibited cell migration, proliferation, and volume regulation (327,328), combined with the presence of these amiloride-sensitive currents in malignant cells and their absence in benign cells, suggests the possibility that these conductances may be useful therapeutic targets. Interestingly, several studies have shown that amiloride and its analogs reduce tumor growth and metastasis in rodent models of cancer, although the relative nonspecificity of this compound, especially at high doses where it inhibits Na ϩ /H ϩ and Na ϩ /Ca 2ϩ exchangers and even a serine protease, makes it difficult to ascribe drug effects directly to ASIC/ENaC inhibition (see Ref.…”

Section: Asics Enacs and Cancermentioning

confidence: 88%

ENaCs and ASICs as therapeutic targets

Qadri

Rooj

Fuller

2012

American Journal of Physiology-Cell Physiology

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The epithelial Na+channel (ENaC) and acid-sensitive ion channel (ASIC) branches of the ENaC/degenerin superfamily of cation channels have drawn increasing attention as potential therapeutic targets in a variety of diseases and conditions. Originally thought to be solely expressed in fluid absorptive epithelia and in neurons, it has become apparent that members of this family exhibit nearly ubiquitous expression. Therapeutic opportunities range from hypertension, due to the role of ENaC in maintaining whole body salt and water homeostasis, to anxiety disorders and pain associated with ASIC activity. As a physiologist intrigued by the fundamental mechanics of salt and water transport, it was natural that Dale Benos, to whom this series of reviews is dedicated, should have been at the forefront of research into the amiloride-sensitive sodium channel. The cloning of ENaC and subsequently the ASIC channels has revealed a far wider role for this channel family than was previously imagined. In this review, we will discuss the known and potential roles of ENaC and ASIC subunits in the wide variety of pathologies in which these channels have been implicated. Some of these, such as the role of ENaC in Liddle's syndrome are well established, others less so; however, all are related in that the fundamental defect is due to inappropriate channel activity.

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Section: Asics Enacs and Cancermentioning

confidence: 88%

ENaCs and ASICs as therapeutic targets

Qadri

Rooj

Fuller

2012

American Journal of Physiology-Cell Physiology

Self Cite

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“…Na-MR imaging, however, yields significant information in unraveling this diagnostic dilemma. The pathophysiologic correlate is a strong relation between NaR:NaT and the tumor proliferation index Ki-67 (On-line Fig 7) on the one hand and the significant role of Na channels in tumor cell division and migration [27][28][29][30][31] on the other hand. NaR:NaT of the CE tumor VOI enabled differentiation of all CE tumors in our patient population except for PA versus AA.…”

Section: Discussionmentioning

confidence: 99%

Improved Brain Tumor Classification by Sodium MR Imaging: Prediction ofIDHMutation Status and Tumor Progression

Biller

Badde

Nagel

et al. 2015

AJNR Am J Neuroradiol

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“…Moreover, AIP treatment did not further decrease ASIC1 currents in cells where ASIC1 was knocked down, suggesting that CaMKII specifically regulates ASIC1 currents. ASIC1 plays a role in GBM cell migration ability (11,20), cell cycle progression (20), and volume regulation (19). However, it is not known whether this CaMKII-mediated activation of ASIC1 affects the ability of GBM cells to migrate.…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies have demonstrated that ASIC1 plays a role in the malignant behavior of glioma cells (11,16,19,20), and that CaMKII regulates many ion channels (21). Therefore, we hypothesized that inhibiting CaMKII and/or ASIC1 activity would reduce the ability of GBM cells to migrate.…”

Section: Camkii-mediated Activation Of Asic1 Contributes To the Abilimentioning

confidence: 97%

Regulation of ASIC1 by Ca2+/calmodulin-dependent protein kinase II in human glioblastoma multiforme

Sun

Zhao

et al. 2013

Oncology Reports

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Abstract. Recent studies have implicated the acid-sensing ion channel 1 (ASIC1), a proton-gated cation channel that belongs to the epithelial sodium channel (ENaC)/Degenerin family, plays an important role in glioma cell migration. Among the ASIC subunits, only ASIC1a has been found be calcium permeable. However, it has not been determined whether Ca 2+ /calmodulin-dependent protein kinase II (CaMKII) regulates ASIC1 in glioblastoma multiforme (GBM). Herein, we report that ASIC1 and CaMKII assemble to form a functional complex at the plasma membrane of GBM cells. We found that migration ability was significantly attenuated in GBM cells that were pre-treated with autocamtide-2-related inhibitory peptide (AIP), a CaMKII-specific inhibitor, or psalmotoxin 1 (PcTX-1), a selective ASIC1 blocker. Furthermore, the inhibitory effect of AIP or PcTX-1 on migration was diminished when ASIC1 was knocked down in GBM cells; when ASIC1 knockdown GBM cells were concurrently treated with these two inhibitors, cell migration was slightly but significantly decreased. Using whole-cell patch-clamp recordings, we detected an amiloride-sensitive current in GBM cells, and this current was significantly inhibited by both PcTX-1 and AIP. Moreover, the magnitude of this current was dramatically decreased when ASIC1 was knocked down in GBM cells. The addition of AIP failed to further decrease the amplitude of this current. Taken together, these data suggest that ASIC1 and CaMKII form a functional complex in GBM cells. Furthermore, it can be concluded that CaMKII regulates the activity of ASIC1, which is associated with the ability of GBM cells to migrate.

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Glioma-specific Cation Conductance Regulates Migration and Cell Cycle Progression

Cited by 86 publications

References 51 publications

ENaCs and ASICs as therapeutic targets

ENaCs and ASICs as therapeutic targets

Improved Brain Tumor Classification by Sodium MR Imaging: Prediction ofIDHMutation Status and Tumor Progression

Regulation of ASIC1 by Ca2+/calmodulin-dependent protein kinase II in human glioblastoma multiforme

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