title: Amblyomin-X induces ER stress, mitochondrial dysfunction, and caspase activation in human melanoma and pancreatic tumor cell.
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 [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.
authors.affiliation: Biochemistry and Biophysics Laboratory, Butantan Institute, Av. Vital Brazil, 1500, São Paulo, SP, 05503-900, Brazil.|Department of Biochemistry, Federal University of São Paulo, São Paulo, SP, Brazil.
authors.forename: Katia L P
authors.initials: KL
authors.lastname: Morais
authors.affiliation: Biochemistry and Biophysics Laboratory, Butantan Institute, Av. Vital Brazil, 1500, São Paulo, SP, 05503-900, Brazil.
authors.forename: Mario Thiego Fernandes
authors.initials: MT
authors.lastname: Pacheco
authors.affiliation: Biochemistry Department, Institute of Chemistry, University of São Paulo, São Paulo, Brazil.
authors.forename: Carolina Maria
authors.initials: CM
authors.lastname: Berra
authors.affiliation: Biochemistry and Biophysics Laboratory, Butantan Institute, Av. Vital Brazil, 1500, São Paulo, SP, 05503-900, Brazil.
authors.forename: Rosemary V
authors.initials: RV
authors.lastname: Bosch
authors.affiliation: Biochemistry and Biophysics Laboratory, Butantan Institute, Av. Vital Brazil, 1500, São Paulo, SP, 05503-900, Brazil.
authors.forename: Juliana Mozer
authors.initials: JM
authors.lastname: Sciani
authors.affiliation: Experimental Oncology Medical Investigation Laboratory - LIM/24, University of São Paulo School of Medicine, São Paulo, SP, Brazil.
authors.forename: Roger
authors.initials: R
authors.lastname: Chammas
authors.affiliation: Experimental Oncology Medical Investigation Laboratory - LIM/24, University of São Paulo School of Medicine, São Paulo, SP, Brazil.
authors.forename: Renata
authors.initials: R
authors.lastname: de Freitas Saito
authors.affiliation: Biochemistry and Biophysics Laboratory, Butantan Institute, Av. Vital Brazil, 1500, São Paulo, SP, 05503-900, Brazil.
authors.forename: Asif
authors.initials: A
authors.lastname: Iqbal
authors.affiliation: Biochemistry and Biophysics Laboratory, Butantan Institute, Av. Vital Brazil, 1500, São Paulo, SP, 05503-900, Brazil. ana.chudzinski@butantan.gov.br.|Department of Biochemistry, Federal University of São Paulo, São Paulo, SP, Brazil. ana.chudzinski@butantan.gov.br.
authors.forename: Ana Marisa
authors.initials: AM
authors.lastname: Chudzinski-Tavassi
mesh_terms: D060829:Arthropod Proteins; D020169:Caspases / Q000378:metabolism*; D045744:Cell Line, Tumor; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D004789:Enzyme Activation; D006801:Humans; D008545:Melanoma / Q000473:pathology*; D008928:Mitochondria / Q000187:drug effects*; D010190:Pancreatic Neoplasms / Q000473:pathology*; D011994:Recombinant Proteins / Q000494:pharmacology; D012471:Salivary Proteins and Peptides / Q000494:pharmacology*
chemical_list: C559369:Amblyomin-X protein, Amblyomma cajennense; D060829:Arthropod Proteins; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D011994:Recombinant Proteins; D012471:Salivary Proteins and Peptides; D020169:Caspases
keywords: Amblyomin-X; Antitumor drug candidate; Endoplasmic reticulum stress; Kunitz-type inhibitor; Proteasome inhibitor