NKCC1 promotes EMT‐like process in GBM via RhoA and Rac1 signaling pathways

Abstract

Glioblastoma is the most common and lethal primary intracranial tumor. As the key regulator of tumor cell volume, sodium‐potassium‐chloride cotransporter 1 (NKCC1) expression increases along with the malignancy of the glioma, and NKCC1 has been implicated in glioblastoma invasion. However, little is known about the role of NKCC1 in the epithelial‐mesenchymal transition‐like process in gliomas. We noticed that aberrantly elevated expression of NKCC1 leads to changes in the shape, polarity, and adhesion of cells in glioma. Here, we investigated whether NKCC1 promotes an epithelial–mesenchymal transition (EMT)‐like process in gliomas via the RhoA and Rac1 signaling pathways. Pharmacological inhibition and knockdown of NKCC1 both decrease the expressions of mesenchymal markers, such as N‐cadherin, vimentin, and snail, whereas these treatments increase the expression of the epithelial marker E‐cadherin. These findings indicate that NKCC1 promotes an EMT‐like process in gliomas. The underlying mechanism is the facilitation of the binding of Rac1 and RhoA to GTP by NKCC1, which results in a significant enhancement of the EMT‐like process. Specific inhibition or knockdown of NKCC1 both attenuate activated Rac1 and RhoA, and the pharmacological inhibitions of Rac1 and RhoA both impair the invasion and migration abilities of gliomas. Furthermore, we illustrated that NKCC1 knockdown abolished the dissemination and spread of glioma cells in a nude mouse intracranial model. These findings suggest that elevated NKCC1 activity acts in the regulation of an EMT‐like process in gliomas, and thus provides a novel therapeutic strategy for targeting the invasiveness of gliomas, which might help to inhibit the spread of malignant intracranial tumors.

Cancer-selective nanoparticles for combinatorial siRNA delivery to primary human GBM in vitro and in vivo

“…Protein targets of particular interest to us include Roundabout homolog 1 (Robol), a protein identified as key to normal and cancer cell migration; [16][17][18] yes-associated protein 1 (YAP1), which promotes growth of GBM cells; [19,20] sodium-potassium-chloride cotransporter (NKCC1), an ion transporter that affects cancer cell migration; [21,22] survivin, an anti-apoptotic gene whose expression in GBM correlates with proliferation [23] and with poor prognosis; [24] and endothelial growth factor receptor (EGFR), an oncogene whose aberrant expression is among the most common mutations in GBM. [25][26][27] Other reports of knockdown of Robo1, [18] YAP1, [28] NKCC1, [21,29] survivin, [30] or EGFR [31] often focus on knockdown of a single gene to isolate cellular mechanisms of GBM survival, growth, and invasion. Of the studies that have used RNAi against one of these targets as a therapeutic strategy, to our knowledge, this is the first report of a delivery system that causes knockdown of all five of these targets at once for GBM therapy.…”

RAC1 Involves in the Radioresistance by Mediating Epithelial-Mesenchymal Transition in Lung Cancer

“…In this report, we found that IR could induce the up-regulation of RAC1 expression and activity via activating the PI3K/AKT signaling pathway (36,(48)(49)(50). Interestingly, IRinduced EMT is regulated by RAC1, a member of the Rho family of small guanosine triphosphatases (GTPases) that has been shown to play a critical role in cytoskeleton reorganization, cell migration and cell survival (51,52). Thus, we raised the possibility that RAC1 might be an important regulator in the process of IR-induced EMT in lung cancer.…”

Targeting the pH Paradigm at the Bedside: A Practical Approach

“…The exchanger works in close association with CAII. Some authors consider NKCC1 expression as a potential pro-tumoral agent [105][106][107][108]. NKCC1 indirectly participates in cytoplasmic alkalinization through its association with the Cl − /CO 3 H − exchanger [109].…”