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

Author(s)

Morais, Katia L. P. ^{[1, 2]} ; Fernandes Pacheco, Mario Thiego ^[2] ; Berra, Carolina Maria ^[3] ; Bosch, Rosemary V. ^[2] ; Sciani, Juliana Mozer ^[2] ; Chammas, Roger ^[4] ; Saito, Renata de Freitas ^[4] ; Iqbal, Asif ^[2] ; Chudzinski-Tavassi, Ana Marisa ^{[1, 2]}

Affiliation

^[1] Univ Fed Sao Paulo, Dept Biochem, Sao Paulo, SP - Brazil

^[2] Butantan Inst, Biochem & Biophys Lab, Ave Vital Brazil 1500, BR-05503900 Sao Paulo, SP - Brazil

^[3] Univ Sao Paulo, Inst Chem, Dept Biochem, Sao Paulo - Brazil

^[4] Univ Sao Paulo, Sch Med, Expt Oncol Med Invest Lab, LIM 24, Sao Paulo, SP - Brazil

• Document type: Journal article
• Source: Molecular and Cellular Biochemistry; v. 415, n. 1-2, p. 119-131, APR 2016.
• Web of Science Citations: 7

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. (AU)

• FAPESP's process: 13/07467-1 - CeTICS - Center of Toxins, Immune-Response and Cell Signaling
• Grantee: Hugo Aguirre Armelin
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC
• FAPESP's process: 11/05969-4 - Investigating the role of dynein in the mechanism of antitumor action of Amblyomin-X in melanoma cells and pancreatic adenocarcinoma
• Grantee: Mario Thiego Fernandes Pacheco
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• FAPESP's process: 98/14307-9 - Center for Applied Toxinology
• Grantee: Hugo Aguirre Armelin
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC
• FAPESP's process: 10/07958-7 - EVALUATION OF THE PRO-APOPTOTIC MECHANISM OF ACTION OF THE AMBLYOMIN-X
• Grantee: Kátia Luciano Pereira Morais
• Support Opportunities: Scholarships in Brazil - Doctorate