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

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

Author Morais, Katia Luciano Pereira Autor UNIFESP Google Scholar
Fernandes Pacheco, Mario Thiego Google Scholar
Berra, Carolina Maria Google Scholar
Bosch, Rosemary V. Google Scholar
Sciani, Juliana Mozer Google Scholar
Chammas, Roger Autor UNIFESP Google Scholar
Saito, Renata de Freitas Google Scholar
Iqbal, Asif Google Scholar
Chudzinski-Tavassi, Ana Marisa Autor UNIFESP Google Scholar
Abstract 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.
Keywords Amblyomin-X
Kunitz-type inhibitor
Proteasome inhibitor
Endoplasmic reticulum stress
Antitumor drug candidate
xmlui.dri2xhtml.METS-1.0.item-coverage Dordrecht
Language English
Sponsor Sao Paulo Research Foundation (FAPESP)
National Council of Technological and Scientific Development (CNPq, INCTTox)
Coordination of Improvement of Higher Education Personnel (CAPES)
Uniao Quimica Farmaceutica Nacional
Grant number FAPESP: 2010/52669-3
FAPESP: 2010/07958-7
FAPESP: 2011/05969-4
FAPESP: CAT/CEPID 1998/14307-9
FAPESP: CETICs 2013/07467-1
Date 2016
Published in Molecular And Cellular Biochemistry. Dordrecht, v. 415, p. 119-131, 2016.
ISSN 0300-8177 (Sherpa/Romeo, impact factor)
Publisher Springer
Extent 119-131
Access rights Open access Open Access
Type Article
Web of Science ID WOS:000373610000011

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