Abstract
Recent studies demonstrated the upregulation of K+ channels in cancer cells. We have previously found that a pore-forming peptide LaFr26, purified from the venom of the Lachesana sp spider, was selectively incorporated into K+ channel expressing hyperpolarized cells. Therefore, it is expected that this peptide would have selective cytotoxicity to hyperpolarized cancer cells. Here we have tested whether LaFr26 and its related peptide, oxyopinin-2b, are selectively cytotoxic to K+ channel expressing cancer cells. These peptides were cytotoxic to the cells, of which resting membrane potential was hyperpolarized. The vulnerabilities of K+ channel-expressing cell lines correlated with their resting membrane potential. They were cytotoxic to lung cancer cell lines LX22 and BEN, which endogenously expressed K+ current. Contrastingly, these peptides were ineffective to glioblastoma cell lines, U87 and T98G, of which membrane potentials were depolarized. Peptides have a drawback, i.e. poor drug-delivery, that hinders their potential use as medicine. To overcome this drawback, we prepared lentiviral vectors that can express these pore-forming peptides and tested the cytotoxicity to K+ channel expressing cells. The transduction with these lentiviral vectors showed autotoxic activity to the channel expressing cells. Our study provides the basis for a new oncolytic viral therapy.
Highlights
Recent studies have shown that some K+ channels are upregulated in cancer cells [1, 2]
We first examined cytotoxicity of chemically synthesized LaFr26 and oxyopinin-2b on 293T cells stably expressing Kir2.1 (56–3). 293T cells were derived from human embryonic kidney, not from the tumor, and the 56–3 cell line was prepared by transfection with lentiviral vectors containing the gene for the Kir2.1 channels’ expression [15]
We examined the cytotoxicity to three cell lines that express different K+ channels, i.e., Kir2.1, TWIK-related K+ channel (TREK-1), and human ether-a-go-related gene (HERG) K+ channel
Summary
Recent studies have shown that some K+ channels are upregulated in cancer cells [1, 2]. Pathological examinations showed upregulation of the two-pore domain type K+ channel, TREK-1 [3], in prostate cancer and of the inwardly rectifying K+ channel, Kir2.1, in lung cancer [4], human ether-a-go-go, HERG, in neuroblastoma [5, 6] whereas surrounding normal cells did not express them. The expression levels of Kir4.1 channel in glioma cells were correlated with clinical stage and chemoresistance [7]. The expression of HERG channel was implicated in cell proliferation and transformation [5]. The upregulated K+ current seemed to play a role in cell proliferation, migration, and cell cycle progression [1, 2].
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