Roles of voltage-gated potassium channels in the maintenance of pancreatic cancer stem cells

Abstract

The targeting of membrane proteins that are activated in cancer stem cells (CSCs) represents one of the key recent strategies in cancer therapy. The present study analyzed ion channel expression profiles and functions in pancreatic CSCs (PCSCs). Cells strongly expressing aldehyde dehydrogenase 1 family member A1 (ALDH1A1) were isolated from the human pancreatic PK59 cell line using fluorescence-activated cell sorting, and PCSCs were identified based on tumorsphere formation. Microarray analysis was performed to investigate the gene expression profiles in PCSCs. ALDH1A1 messenger RNA levels were higher in PCSCs compared with non-PCSCs. PCSCs were resistant to 5-fluorouracil and capable of redifferentiation. The results of the microarray analysis revealed that gene expression related to ion channels, including voltage-gated potassium channels (Kv), was upregulated in PCSCs compared with non-PCSCs. 4-Aminopyridine (4-AP), a potent Kv inhibitor, exhibited greater cytotoxicity in PCSCs compared with non-PCSCs. In a xenograft model in nude mice, tumor volumes were significantly lower in mice inoculated with PK59 cells pre-treated with 4-AP compared with those in mice injected with non-treated cells. The present results identified a role of Kv in the persistence of PCSCs and suggested that the Kv inhibitor 4-AP may have potential as a therapeutic agent for pancreatic carcinoma.