APETx4, a Novel Sea Anemone Toxin and a Modulator of the Cancer-Relevant Potassium Channel KV10.1.
作者： Lien Moreels , Steve Peigneur , Diogo T Galan , Edwin De Pauw , Lászlo Béress
DOI: 10.3390/MD15090287
关键词:
摘要: The human ether-a-go-go channel (hEag1 or KV10.1) is a cancer-relevant voltage-gated potassium that overexpressed in majority of tumors. Peptides are able to selectively inhibit this can be lead compounds the search for new anticancer drugs. Here, we report activity-guided purification and electrophysiological characterization novel KV10.1 inhibitor from sea anemone Anthopleura elegantissima. Purified fractions were screened inhibitory activity on by measuring whole-cell currents as expressed Xenopus laevis oocytes using two-microelectrode voltage clamp technique. Fractions showed Kv10.1 further purified RP-HPLC. amino acid sequence peptide was determined combination MALDI- LIFT-TOF/TOF MS/MS CID-ESI-FT-ICR high similarity with APETx1 APETx3 therefore named APETx4. Subsequently, electrophysiologically characterized KV10.1. selectivity toxin investigated an array ion channels, including cardiac ether-a-go-go-related gene (hERG Kv11.1). inhibits IC50 value 1.1 μM. In presence similar concentration, shift activation curve towards more positive potentials observed. Similar effect gating modifier hERG, inhibition isolated reduced at voltages seems keep closed state. Although also induces effects other KV NaV it exhibits no significant hERG. Moreover, APETx4 concentration-dependent cytotoxic proapoptotic various cancerous noncancerous cell lines. This newly identified used tool characterize oncogenic scaffold design synthesis potent safer
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Sergey Dyshlovoy, Friedemann Honecker, Marine Compounds and Cancer: Where Do We Stand? Marine Drugs. ,vol. 13, pp. 5657- 5665 ,(2015) , 10.3390/MD13095657
M. J. Saganich, E. Machado, B. Rudy, Differential Expression of Genes Encoding Subthreshold-Operating Voltage-Gated K+Channels in Brain The Journal of Neuroscience. ,vol. 21, pp. 4609- 4624 ,(2001) , 10.1523/JNEUROSCI.21-13-04609.2001
Luis A Pardo, Donato del Camino, Araceli Sánchez, Frauke Alves, Andrea Brüggemann, Synnöve Beckh, Walter Stühmer, Oncogenic potential of EAG K(+) channels. The EMBO Journal. ,vol. 18, pp. 5540- 5547 ,(1999) , 10.1093/EMBOJ/18.20.5540
Richard J. Lewis, Maria L. Garcia, Therapeutic potential of venom peptides Nature Reviews Drug Discovery. ,vol. 2, pp. 790- 802 ,(2003) , 10.1038/NRD1197
Steve Peigneur, László Béress, Carolina Möller, Frank Marí, Wolf‐Georg Forssmann, Jan Tytgat, A natural point mutation changes both target selectivity and mechanism of action of sea anemone toxins The FASEB Journal. ,vol. 26, pp. 5141- 5151 ,(2012) , 10.1096/FJ.12-218479
S. Martin, C. Lino de Oliveira, F. Mello de Queiroz, L.A. Pardo, W. Stühmer, E. Del Bel, Eag1 potassium channel immunohistochemistry in the CNS of adult rat and selected regions of human brain. Neuroscience. ,vol. 155, pp. 833- 844 ,(2008) , 10.1016/J.NEUROSCIENCE.2008.05.019
Marc Schumacher, Mareike Kelkel, Mario Dicato, Marc Diederich, Gold from the sea: marine compounds as inhibitors of the hallmarks of cancer. Biotechnology Advances. ,vol. 29, pp. 531- 547 ,(2011) , 10.1016/J.BIOTECHADV.2011.02.002
Guadalupe-Miroslava Suarez-Jimenez, Armando Burgos-Hernandez, Josafat-Marina Ezquerra-Brauer, Bioactive peptides and depsipeptides with anticancer potential: sources from marine animals. Marine Drugs. ,vol. 10, pp. 963- 986 ,(2012) , 10.3390/MD10050963
Sylvie Diochot, Anne Baron, Lachlan D Rash, Emmanuel Deval, Pierre Escoubas, Sabine Scarzello, Miguel Salinas, Michel Lazdunski, A new sea anemone peptide, APETx2, inhibits ASIC3, a major acid-sensitive channel in sensory neurons The EMBO Journal. ,vol. 23, pp. 1516- 1525 ,(2004) , 10.1038/SJ.EMBOJ.7600177
David Gómez-Varela, Esther Zwick-Wallasch, Hendrik Knötgen, Araceli Sánchez, Thore Hettmann, Dmitri Ossipov, Rüdiger Weseloh, Constanza Contreras-Jurado, Mike Rothe, Walter Stühmer, Luis A. Pardo, Monoclonal antibody blockade of the human Eag1 potassium channel function exerts antitumor activity. Cancer Research. ,vol. 67, pp. 7343- 7349 ,(2007) , 10.1158/0008-5472.CAN-07-0107