Cancer as a channelopathy: ion channels and pumps in tumor development and progression

Most cancers are treated by surgical resection, chemotherapy, and radiation therapy. However due to the prevalence of cancer relapse with treatment resistance, novel molecular targets must be identified for the development of alternative therapies. Despite the growing evidence of aberrant expression and function of ion channels in oncology, development of cancer treatment using ion channel targeting compounds is still at an early stage. Studies have shown that some VGSC blockers can inhibit cell behaviors associated with metastasis. For example, the anticonvulsant phenytoin suppressed migration of prostate cancer cells (Fraser et al., 2003), and also inhibited migration and invasion in metastatic breast cancer cells (Yang et al., 2012). Riluzole, which is both a VGSC blocker and metabotropic glutamate receptor inhibitor, reduced the breast cancer tumor volume in mice, and suppressed metabolic activity of tumors in patients with stage III and IV melanoma (Yip et al., 2009). The KV10.1 EAG1 channel has been closely studied as a target for cancer therapy, since EAG1 overexpression is associated with tumorigenic potential, and its expression is correlated with poor patient survival in multiple cancer types (Pardo and Stühmer, 2008). The small molecule EAG1 blocker astemizole reduced EAG1-expressing cancer cell growth in vitro and in vivo (Downie et al., 2008). A highly specific extracellular epitope-targeting EAG1 monoclonal antibody exhibited antitumor activity in a mouse model (Gómez-Varela et al., 2007). T-type Ca2+ channels have also been suggested as a potential therapeutic target for certain brain tumors.

Mibefradil, a calcium channel inhibitor, was found to inhibit proliferation in human glioma and neuroblastoma cells, and overexpression of T-type Ca2+ channel protein doubled the proliferation rate while antisense treatment reduced the proliferation rate of these cells (Panner et al., 2005). The Na,K-ATPase is another potential target for cancer therapy. Human glioblastoma cells that are resistant to the chemotherapy drug temozolomide (TMZ) show a higher expression of Na,K-ATPase α2- and α3-subunits compared to TMZ-sensitive cells and astrocytes. These cells were also sensitive to ouabain at low concentrations, and knockdown of the α3-subunit sensitized the cells to TMZ (Chen et al., 2014). Judging from the large number of ion channels that are altered in cancers, it is clear that understanding more about ion channels and pumps and how they contribute to cancer progression could reveal new therapeutic targets for many different cancers. The findings discussed above provide proof of principle that ion channels are effective targets for cancer therapy.

Increasing evidence suggests that ion channels and pumps are involved in the regulation of cell proliferation and migration, and channel proteins have been shown to form macromolecular complexes with cell adhesion molecules and other signaling proteins. As these roles of ion channels and pumps are further elucidated, it is being increasingly suggested that regulation of ion channels and pumps could contribute to cancer progression. Here we discussed that aberrant expression and function of several types of ion channels and pumps have been found in multiple cancers including brain cancer, and in particular, glioblastoma. Knowing that these proteins are involved in multiple malignant characteristics of multiple cancers, ion channels and pumps could be potential targets for therapy.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

ASIC, Acid-sensing ion channel; BK, Big conductance channel; CDK, Cyclin dependent kinase; CFTR, Cystic fibrosis transmembrane conductance regulator; EAG1, Voltage gated eag related subfamily H, member 1; ECM, Extracellular matrix; EGF, Epidermal growth factor; EGFR, Epidermal growth factor receptor; ER, Endoplasmic reticulum; FAK, Focal adhesion kinase; GIRK, G protein-gated inwardly rectifying K+ channel; HER2, Human epidermal growth factor receptor 2; IK, Intermediate conductance channel; K2P, Two-pore domain potassium channel; KATP, ATP-sensitive K+ channels; KCa, Calcium-activated potassium channel; Kir, Inward rectifying potassium channel; KV, Voltage-gated potassium channel; MDCK-F, transformed Madin-Darby canine kidney; Na, K-ATPase, Sodium potassium ATPase; NHE1, Na+/H+ exchanger; NKCC, Na+, K+, 2Cl− cotransporter; PI3-kinase, Phosphatidylinositol 3-kinase; PMCA, Plasma Membrane Ca2+ ATPase; RGD, Arginine-Glycine-Aspartate; SERCA, Sarcoplasmic and endoplasmic reticulum Ca-ATPase; SK, Small conductance channel; TMZ, Temozolomide; TRP, Transient receptor potential channel; VEGFR, Vascular endothelial growth factor receptor; VGSC, Voltage gated sodium channel.