Ion transporters in brain tumors

Abstract

Ion transporters are important in regulation of ionic homeostasis, cell volume, and cellular signal transduction under physiological conditions. They have recently emerged as important players in cancer progression. In this review, we discussed two important ion transporter proteins, sodium-potassium-chloride cotransporter isoform 1 (NKCC-1) and sodium-hydrogen exchanger isoform 1 (NHE-1) in Glioblastoma multiforme (GBM) and other malignant tumors. NKCC-1 is a Na(+)- dependent Cl(-) transporter that mediates the movement of Na(+), K(+), and Cl(-) ions across the plasma membrane and maintains cell volume and intracellular K(+) and Cl(-) homeostasis. NHE-1 is a ubiquitously expressed cell membrane protein which regulates intracellular pH (pH(i)) and extracellular pH (pH(e)) homeostasis and cell volume. Here, we summarized recent pre-clinical experimental studies on NKCC-1 and NHE-1 in GBM and other malignant tumors, such as breast cancer, hepatocellular carcinoma, and lung cancer cells. These studies illustrated that pharmacological inhibition or down-regulation of these ion transporter proteins reduces proliferation, increases apoptosis, and suppresses migration and invasion of cancer cells. These new findings reveal the potentials of these ion transporters as new targets for cancer diagnosis and/or treatment.

Figure 1. Roles of NKCC-1 in counteract against the TMZ-mediated glioma apoptosis

A schematic model illustrates that temozolomide (TMZ) triggers loss of K⁺_i, Cl_i and apoptotic volume decrease (AVD), and leads to apoptotic cell death in glioblastoma cancer cells. In response to TMZ, the novel Cl⁻/volume-sensitive regulatory kinases WNK-mediated signaling transduction pathway is stimulated and activates NKCC-1 protein by phosphorylation. Activation of NKCC-1 accumulates intracellular Na⁺, K⁺, and Cl⁻ and obligated water molecules (regulatory volume increase, RVI) to counteract ionic dysregulation and AVD and promote cell survival of the TMZ-treated cells. In contrast, inhibition of NKCC-1 activity with bumetanide facilitates loss of intracellular K⁺, Cl⁻ and AVD, thus sensitizes glioma cells to the TMZ-mediated apoptosis (adopted from Algharabil, et al [48]).

Figure 2. Regulation of NKCC-1 and NHE-1 in cancer cell death and migration/invasion

A schematic diagram illustrates important roles of NKCC-1 and NHE-1 in regulation of cancer cell survival and migration/invasion. In response to stimuli, WNKs/OSR1 are major upstream regulators of NKCC1, while ERK 1/2 and p38 MAPK signaling pathway is involved in activation of NHE-1. NKCC-1 and NHE-1 mediate regulatory volume increase (RVI) to against apoptosis and promote cell survival. Direct interaction between ERM-NKCC-1 or ERM-NHE-1 contributes to cytoskeletal rearrangement which affects cell migration. Activation of NHE-1 not only leads to cytosolic alkalinization and inhibits apoptosis, but also increases cell migration/invasion by mediating extracellular acidification and stimulating release of MMPs.