Cell-Permeable Gomesin Peptide Promotes Cell Death by Intracellular Ca2+ Overload

Author(s):Show less -

Paredes-Gamero, Edgar J. ^{[1, 2]} ; Casaes-Rodrigues, Rafael L. ^[1] ; Moura, Gioconda E. D. D. ^[1] ; Domingues, Tatiana M. ^[2] ; Buri, Marcus V. ^[2] ; Ferreira, Victor H. C. ^[3] ; Trindade, Edvaldo S. ^[3] ; Moreno-Ortega, Ana J. ^[4] ; Cano-Abad, Maria F. ^[4] ; Nader, Helena B. ^[1] ; Ferreira, Alice T. ^[2] ; Miranda, Antonio ^[2] ; Justo, Giselle Z. ^{[1, 5]} ; Tersariol, Ivarne L. S. ^{[1, 6]}

Affiliation

^[1] Univ Fed Sao Paulo, Dept Bioquim, BR-04044020 Sao Paulo - Brazil

^[2] Univ Fed Sao Paulo, Dept Biofis, BR-04044020 Sao Paulo - Brazil

^[3] Univ Fed Parana, Dept Biol Celular, BR-81531990 Curitiba, Parana - Brazil

^[4] Univ Autonoma Madrid, Inst Teofilo Hernando, Inst Invest Sanitaria, Hosp Univ Princesa, Serv Farmacol Clin, Madrid - Spain

^[5] Univ Fed Sao Paulo, Dept Ciencias Biol, Diadema, SP - Brazil

^[6] Univ Mogi das Cruzes, Ctr Interdisciplinar Invest Bioquim, Mogi Das Cruzes, SP - Brazil

• Document type: Journal article
• Source: MOLECULAR PHARMACEUTICS; v. 9, n. 9, p. 2686-2697, SEP 2012.
• Web of Science Citations: 24

Abstract

In recent years, the antitumoral activity of antimicrobial peptides (AMPs) has been the goal of many research studies. Among AMPs, gomesin (Gm) displays antitumor activity by unknown mechanisms. Herein, we studied the cytotoxicity of Gm in the Chinese hamster ovary (CHO) cell line. Furthermore, we investigated the temporal ordering of organelle changes and the dynamics of Ca2+ signaling during Gm-induced cell death. The results indicated that Gm binds to the plasma membrane and rapidly translocates into the cytoplasm. Moreover, 20 mu M Gm increases the cytosolic Ca2+ and induces membrane permeabilization after 30 min of treatment. Direct Ca2+ measurements in CHO cells transfected with the genetically encoded D1-cameleon to the endoplasmic reticulum (ER) revealed that Gm induces ER Ca2+ depletion, which in turn resulted in oscillatory mitochondrial Ca2+ signal, as measured in cells expressing the genetically encoded probe to the mitochondrial matrix (mit)Pericam. This leads to mitochondria disruption, loss of mitochondrial membrane potential and increased reactive oxygen species prior to membrane permeabilization. Gm-induced membrane permeabilization by a Ca2+-dependent pathway involving Gm translocation into the cell, ER Ca2+ depletion and disruption, mitochondrial Ca2+ overload and oxidative stress. (AU)