KCa3.1 channels are involved in the infiltrative behavior of glioblastoma in vivo

Abstract

Glioblastoma multiforme (GBM) is a diffuse brain tumor characterized by high infiltration in the brain parenchyma rendering the tumor difficult to eradicate by neurosurgery. Efforts to identify molecular targets involved in the invasive behavior of GBM suggested ion channel inhibition as a promising therapeutic approach. To determine if the Ca2+-dependent K+ channel KCa3.1 could represent a key element for GBM brain infiltration, human GL-15 cells were xenografted into the brain of SCID mice that were then treated with the specific KCa3.1 blocker TRAM-34 (1-((2-chlorophenyl) (diphenyl)methyl)-1H-pyrazole). After 5 weeks of treatment, immunofluorescence analyses of cerebral slices revealed reduced tumor infiltration and astrogliosis surrounding the tumor, compared with untreated mice. Significant reduction of tumor infiltration was also observed in the brain of mice transplanted with KCa3.1-silenced GL-15 cells, indicating a direct effect of TRAM-34 on GBM-expressed KCa3.1 channels. As KCa3.1 channels are also expressed on microglia, we investigated the effects of TRAM-34 on microglia activation in GL-15 transplanted mice and found a reduction of CD68 staining in treated mice. Similar results were observed in vitro where TRAM-34 reduced both phagocytosis and chemotactic activity of primary microglia exposed to GBM-conditioned medium. Taken together, these results indicate that KCa3.1 activity has an important role in GBM invasiveness in vivo and that its inhibition directly affects glioma cell migration and reduces astrocytosis and microglia activation in response to tumor-released factors. KCa3.1 channel inhibition therefore constitutes a potential novel therapeutic approach to reduce GBM spreading into the surrounding tissue.

SK4 channels modulate Ca2+ signalling and cell cycle progression in murine breast cancer

“…Members of the Ca 2+ ‐activated K + channel (K Ca ) family, that is BK (also known as K Ca 1.1, Maxi‐K or Slo1) and SK4 (also known as K Ca 3.1 or IK), have been implicated in the progression of malignant diseases including but not limited to gliomas (D'Alessandro et al ., 2013; Liu et al ., 2002; Turner et al ., 2014), clear cell renal cell carcinoma (Rabjerg et al ., 2015) and breast cancer (Haren et al ., 2010; Oeggerli et al ., 2012; Thurber et al ., 2017). Aberrant K + efflux via oncogenic K Ca channels may affect multiple parameters in the breast tumour cell such as membrane potential, cytosolic Ca 2+ ([Ca 2+ ] i ), pH and cell volume (Huang and Jan, 2014; Huber, 2013).…”

Molecular Mechanisms of Glioma Cell Motility

“…The KCa family of Ca 2 + -activated K + channels, especially KCa3.1, is overexpressed in 32% of the glioma patients, and its expression correlates with patient survival (126). KCa3.1 is localized at the leading edge of migrating cells, and its inhibition results in reduced migration (127,128). The bradykinin receptor B 2 (B 2 R) is also expressed at the leading edge of migrating glioma cells.…”

Targeting potassium channels in cancer

“…For the few medulloblastoma cells with deficient EAG2 function that escape the G2 arrest and enter mitosis, they fail to achieve proper mitotic morphology and encounter mitotic catastrophe. The medulloblastoma tumors with deficient EAG2 function display markedly impaired (D'Alessandro et al, 2013). BK and SK channels can also promote breast cancer cell migration and are implicated in metastasis (Khaitan et al, 2009;Chantôme et al, 2013).…”