Amblyomin-X induces ER stress, mitochondrial dysfunction, and caspase activation in human melanoma and pancreatic tumor cell

• Autor(a) principal: Morais, Katia Luciano Pereira [UNIFESP]
• Data de Publicação: 2016
• Outros Autores: Fernandes Pacheco, Mario Thiego, Berra, Carolina Maria, Bosch, Rosemary V., Sciani, Juliana Mozer, Chammas, Roger [UNIFESP], Saito, Renata de Freitas, Iqbal, Asif, Chudzinski-Tavassi, Ana Marisa [UNIFESP]
• Tipo de documento: Artigo
• Idioma: eng
• Título da fonte: Repositório Institucional da UNIFESP
• Texto Completo: http://dx.doi.org/10.1007/s11010-016-2683-4; https://repositorio.unifesp.br/handle/11600/56153
• topic: Amblyomin-X; Kunitz-type inhibitor; Proteasome inhibitor; Endoplasmic reticulum stress; Antitumor drug candidate

During the last two decades, new insights into proteasome function and its role in several human diseases made it a potential therapeutic target. In this context, Amblyomin-X is a Kunitz-type FXa inhibitor similar to endogenous tissue factor pathway inhibitor (TFPI) and is a novel proteasome inhibitor. Herein, we have demonstrated Amblyomin-X cytotoxicity to different tumor cells lines such as pancreatic (Panc1, AsPC1BxPC3) and melanoma (SK-MEL-5 and SK-MEL-28). Of note, Amblyomin-X was not cytotoxic to normal human fibroblast cells. In addition, Amblyomin-X promoted accumulation of ER stress markers (GRP78 and GADD153) in sensitive (SK-MEL-28) and bortezomib-resistant (Mia-PaCa-2) tumor cells. The intracellular calcium concentration [Ca2+] (i) was slightly modulated in human tumor cells (SK-MEL-28 and Mia-PaCa-2) after 24 h of Amblyomin-X treatment. Furthermore, Amblyomin-X induced mitochondrial dysfunction, cytochrome-c release, PARP cleavage, and activation of caspase cascade in both human tumor (SK-MEL-28 and Mia-PaCa-2) cells. These investigations might help in further understanding of the antitumor properties of Amblyomin-X.