Figure 7. A schematic model of NKCC1 in TMZ-mediated apoptosis.

TMZ triggers loss of K⁺_i, Cl⁻_i and apoptotic volume decrease (AVD), and leads to apoptotic cell death in glioblastoma cancer cells. NKCC1 activity may be stimulated via the novel Cl⁻/volume-sensitive regulatory kinases WNK-mediated signaling transduction pathway in response to TMZ. Activation of NKCC1 in TMZ-treated cells accumulate Na⁺_i, K⁺_i, and Cl⁻_i and obligated water molecules (regulatory volume increase, RVI) to counteract ionic dysregulation and AVD and promote cell survival. Inhibition of NKCC1 activity with BMT would facilitate loss of K⁺_i, Cl⁻_i and AVD, thus augments glioma cells to TMZ-mediated apoptosis.