Journal
MOLECULAR PHARMACEUTICS
Volume 9, Issue 9, Pages 2686-2697Publisher
AMER CHEMICAL SOC
DOI: 10.1021/mp300251j
Keywords
antimicrobial peptide; gomesin; membrane permeabilization; calcium; endoplasmic reticulum; mitochondria
Funding
- Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP) [2009/54869-2]
- Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq)
- CAPES
- Consolodacion de grupos UAM-CAM [1004040047]
- FPU from Ministerio de Educacion, Spain [AP2009-0343]
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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.
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