Estudo do papel da dineína no mecanismo de ação antitumoral do Amblyomin-X em células de melanoma e adenocarcinoma de pâncreas

Abstract

Hematophagous animals are sources of natural anticoagulants, since, for feeding, they need to maintain fluid blood in their digestive tract and therefore may contain a series of physiologically active molecules. From the construction of a cDNA library from the salivary glands of the Amblyomma cajennense tick, it was identified a transcript that encodes a serine protease inhibitor with a Kunitz-type domain similar to the endogenous TFPI inhibitor. The protein showed an inhibitory effect on the coagulation factor FXa and was isolated and produced in recombinant form, being named Amblyomin-X. Furthermore, the recombinant protein exerted pro-apoptotic effects in tumor cells as well as anti-angiogenic activity, tumor regression and decreased metastasis. Until now, it was not identified cytotoxic effects of AmblyominX in non-malignant or normal cells, such as fibroblasts. Among the activities described in this new molecule, we emphasize its ability to inhibit the proteasome system and to induce an increase in gene expression of the dynein cytoplasmic 1 light-intermediate chain 2 in microarray analysis in melanoma (SK-MEL-28) and pancreatic adenocarcinoma (MIA PaCa-2) human cells. The dynein is a molecular motor that plays an important role in all eukaryotic cells in transport of proteins, organelles and vesicles, and also the positioning of the nucleus, and the mitotic spindle pole and microtubules. This study is proposed to investigate the role of dynein in the antitumor mechanism of action of Amblyomin-X, from its uptake by the cell towards to its target as well as the biological effects triggered by this novel molecule linked to the proteasome inhibition.