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

• Published in: Molecular and cellular biochemistry Vol. 415; no. 1-2; pp. 119 - 131
• Main Authors: Morais, Katia L. P., Pacheco, Mario Thiego Fernandes, Berra, Carolina Maria, Bosch, Rosemary V., Sciani, Juliana Mozer, Chammas, Roger, de Freitas Saito, Renata, Iqbal, Asif, Chudzinski-Tavassi, Ana Marisa
• Format: Journal Article
• Language: English
• Published: New York Springer US 01.04.2016; Springer; Springer Nature B.V
• Subjects: Biochemistry; Biomedical and Life Sciences; Cardiology; Caspases - metabolism; Cell Line, Tumor; Cytotoxicity; Endoplasmic Reticulum Stress - drug effects; Enzyme Activation; Enzymes; Health aspects; Humans; Inhibitor drugs; Life Sciences; Medical Biochemistry; Melanoma; Melanoma - pathology; Mitochondria - drug effects; Oncology; Pancreatic cancer; Pancreatic Neoplasms - pathology; Recombinant Proteins - pharmacology; Salivary Proteins and Peptides - pharmacology; Antitumor drug candidate; Kunitz-type inhibitor; Amblyomin-X; Proteasome inhibitor; Endoplasmic reticulum stress
• ISSN: 0300-8177; 1573-4919
• DOI: 10.1007/s11010-016-2683-4

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 [Ca 2+ ] 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.