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

Oncogenic signalling via Ca2+ -activated K+ channels of intermediate conductance (SK4, also known as KCa 3.1 or IK) has been implicated in different cancer entities including breast cancer. Yet, the role of endogenous SK4 channels for tumorigenesis is unclear. Herein, we generated SK4-negative tumours by crossing SK4-deficient (SK4 KO) mice to the polyoma middle T-antigen (PyMT) and epidermal growth factor receptor 2 (cNeu) breast cancer models in which oncogene expression is driven by the retroviral promoter MMTV. Survival parameters and tumour progression were studied in cancer-prone SK4 KO in comparison with wild-type (WT) mice and in a syngeneic orthotopic mouse model following transplantation of SK4-negative or WT tumour cells. SK4 activity was modulated by genetic or pharmacological means using the SK4 inhibitor TRAM-34 in order to establish the role of breast tumour SK4 for cell growth, electrophysiological signalling, and [Ca2+ ]i oscillations. Ablation of SK4 and TRAM-34 treatment reduced the SK4-generated current fraction, growth factor-dependent Ca2+ entry, cell cycle progression and the proliferation rate of MMTV-PyMT tumour cells. In vivo, PyMT oncogene-driven tumorigenesis was only marginally affected by the global lack of SK4, whereas tumour progression was significantly delayed after orthotopic implantation of MMTV-PyMT SK4 KO breast tumour cells. However, overall survival and progression-free survival time in the MMTV-cNeu mouse model were significantly extended in the absence of SK4. Collectively, our data from murine breast cancer models indicate that SK4 activity is crucial for cell cycle control. Thus, the modulation of this channel should be further investigated towards a potential improvement of existing antitumour strategies in human breast cancer.

Ionizing radiation induces migration of glioblastoma cells by activating BK K(+) channels.

BACKGROUND AND PURPOSE: Glioblastoma cells express high levels of Ca(2+)-activated BK K(+) channels which have been proposed to be indispensable for glioblastoma proliferation and migration. Since migration of glioblastoma cells is reportedly stimulated by ionizing radiation (IR), we tested for an IR-induced increase in BK channel activity and its effect on cell migration. MATERIALS AND METHODS: T98G and U87MG cells were X-ray-irradiated with 0-2 Gy, BK channel activity was assessed by patch-clamp recording, migration by trans-well migration assay, and activation of the Ca(2+)/calmodulin-dependent kinase II (CaMKII) by immunoblotting. RESULTS: IR dose-dependently stimulated migration of glioblastoma cells which was sensitive to the BK channel inhibitor paxilline. Ca(2+)-permeabilization of T98G cells activated up to 350 BK channels per cells. Importantly, IR stimulated an increase in BK channel open probability but did not modify the total number of channels. Moreover, IR activated CaMKII in a paxilline-sensitive manner. Finally, inhibition of CaMKII by KN-93 abolished the IR-stimulated migration. CONCLUSIONS: We conclude that IR stimulates BK channel activity which results in activation of CaMKII leading to enhanced glioblastoma cell migration.