Date Published: April 12, 2019
Publisher: Public Library of Science
Author(s): Masayoshi Okada, Ernesto Ortiz, Gerardo Corzo, Lourival D. Possani, Israel Silman.
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.
Recent studies have shown that some K+ channels are upregulated in cancer cells [1, 2]. For instance, pathological examinations showed upregulation of the two-pore domain type K+ channel, TREK-1 , in prostate cancer and of the inwardly rectifying K+ channel, Kir2.1, in lung cancer , 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 . The expression of HERG channel was implicated in cell proliferation and transformation . The upregulated K+ current seemed to play a role in cell proliferation, migration, and cell cycle progression [1, 2].