ENaC/DEG in Tumor Development and Progression

Liu, Cui; Zhu, Lingling; Xu, Si; Ji, Hong; Li, Xiu Min

doi:10.7150/jca.15693

Cited by 31 publications

(30 citation statements)

References 38 publications

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“…This amiloride-sensitive sodium conductance is presented in high-grade (grades III and IV) tumors and is not observed in normal astrocytes or low-grade gliomas. ASICs and EnaC channels are known to participate in the regulation of many essential processes in GBM cells [19,20], and in malignant and normal astrocytes [19,20,38]. The activation of these channels leads to the inhibition of apoptosis and stimulates the proliferation, migration and invasion of glioma and carcinoma cells, and contrary, their inhibition leads to suppression of tumor growth [19].…”

Section: Discussionmentioning

confidence: 99%

Mambalgin-2 Induces Cell Cycle Arrest and Apoptosis in Glioma Cells via Interaction with ASIC1a

Bychkov

Shulepko

Osmakov

et al. 2020

Cancers

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Gliomas are fast growing and highly invasive brain tumors, characterized by tumor microenvironment acidification that drives glioma cell growth and migration. Channels containing Acid-sensing Ion Channel 1a subunit (ASIC1a) mediate amiloride-sensitive cation influx in late stage glioma cells, but not in normal astrocytes. Thus, selective targeting of ASIC1a can be a perspective strategy for glioma treatment. Here, ASIC1a expression in U251 MG and A172 glioma cells, but not in normal astrocytes, was demonstrated. Recombinant analog of mambalgin-2 from black mamba Dendroaspis polylepis inhibited amiloride-sensitive currents at ASIC1a both in Xenopus laevis oocytes and in U251 MG cells, while its mutants with impaired activity towards this channel did not. Mambalgin-2 inhibited U251 MG and A172 glioma cells growth with EC50 in the nanomolar range without affecting the proliferation of normal astrocytes. Notably, mambalgin-2 mutants did not affect glioma cell proliferation, pointing on ASIC1a as the main molecular target of mambalgin-2 in U251 MG and A172 cells. Mambalgin-2 induced a cell cycle arrest, inhibited Cyclin D1 and cyclin-dependent kinases (CDK) phosphorylation and caused apoptosis in U251 MG and A172 cells. Moreover, mambalgin-2 inhibited the growth of low-passage primary cells from a patient with glioblastoma. Altogether, our data point to mambalgin-2 as a useful hit for the development of new drugs for glioma treatment.

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Section: Discussionmentioning

confidence: 99%

Mambalgin-2 Induces Cell Cycle Arrest and Apoptosis in Glioma Cells via Interaction with ASIC1a

Bychkov

Shulepko

Osmakov

et al. 2020

Cancers

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“…This function might be attained by impinging upon classical AKT targets and contributing to their phosphorylation, or by controlling known SGK targets that impact cell proliferation, such as the Ca 2+ release-activated Ca 2+ channel (I CRAC ) (35), potassium channels such as Kv1.3 (36), proton exchangers such as NHE3 (37), or the epithelial sodium channel, ENAC (38). Alternatively, SGK1 could phosphorylate still unknown targets, which may contribute to neoplastic transformation either directly, or by controlling additional downstream players.…”

Section: Discussionmentioning

confidence: 99%

SGK1 Is a Critical Component of an AKT-Independent Pathway Essential for PI3K-Mediated Tumor Development and Maintenance

et al. 2017

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Activation of the PI3K-AKT signaling cascade is a common critical event during malignant transformation. In this study, we used thyroid gland epithelial cells and a series of genetically engineered mouse strains as model systems to demonstrate that, while necessary, AKT activation is not sufficient for PI3K-driven transformation. Instead, transformation requires the activity of the PDK1-regulated AGC family of protein kinases. In particular, SGK1 was found to be essential for proliferation and survival of thyroid cancer cells harboring PI3K-activating mutations. Notably, co-targeting SGK1 and AKT resulted in significantly higher growth suppression than inhibiting either PI3K or AKT alone. Overall, these findings underscore the clinical relevance of AKT-independent pathways in tumors driven by genetic lesions targeting the PI3K cascade.

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“…Additionally, SGK1-controlled proton exchangers such as NHE3 have been associated with the control of lysosome trafficking in prostate cancer cells (Steffan, Williams, Welbourne, & Cardelli, 2010), and ENAC activity has been shown to mediate a variety of processes, including cancer cell proliferation and migration (Liu, Zhu, Xu, Ji, & Li, 2016). …”

Section: Sgk1 and Cancermentioning

confidence: 99%

Sgk1

Cristofano

2017

Current Topics in Developmental Biology

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Activation of the PI3K pathway is central to a variety of physiological and pathological processes. In these contexts, AKT is classically considered the de facto mediator of PI3K-dependent signaling. However, in recent years, accumulating data point to the existence of additional effectors of PI3K activity, parallel to and independent of AKT, that play critical and unique roles in mediating different developmental, homeostatic, and pathological processes. In this review, I summarize and discuss our current understanding of the function of the serine/threonine kinase SGK1 as a downstream effector of PI3K, and try to separate targets and pathways validated as uniquely SGK1-dependent from those shared with AKT.

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ENaC/DEG in Tumor Development and Progression

Cited by 31 publications

References 38 publications

Mambalgin-2 Induces Cell Cycle Arrest and Apoptosis in Glioma Cells via Interaction with ASIC1a

Mambalgin-2 Induces Cell Cycle Arrest and Apoptosis in Glioma Cells via Interaction with ASIC1a

SGK1 Is a Critical Component of an AKT-Independent Pathway Essential for PI3K-Mediated Tumor Development and Maintenance

Sgk1

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