Heparan sulfate binds the extracellular Annexin A1 and blocks its effects on pancreatic cancer cells.

Raffaella Belvedere, Nunzia Novizio, Emanuela Pessolano, Alessandra Tosco, Daniela Eletto, Amalia Porta, Pietro Campiglia, Mauro Perretti, Amelia Filippelli, Antonello Petrella

Biochemical pharmacology 2020 Dec

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In pancreatic cancer (PC) progression the protein Annexin A1 (ANXA1) has been described as oncogenic factor. Thus, the need to inhibit its action, mainly the extracellular form, has become an appealing cue for the anti-cancer research. Heparan sulfate (HS) is a glycosaminoglycan of the extracellular matrix known to bind several molecules, as growth factors and cytokines, generating a kind of reservoir in the extracellular environment. Here, we started our study by showing the physical calcium-dependent interaction between HS and ANXA1 as both full-length protein and N-terminal portion, Ac2-26 by biophysical techniques. HS is able to inhibit the migration/invasion process of human PC MIA PaCa-2 cells and partially revert their mesenchymal phenotype as reported through the expression of specific protein markers and the growth in colonies and in 3D-spheroids. Furthermore, both on MIA PaCa-2 and PANC-1 cells, HS blocks the effects of Ac2-26, which enhances the aggressive behavior of PC cells if added alone. These effects appear evident also on endothelial cells whose activation is promoted by Ac2-26 but not in presence of HS. Thus, the interference of the interaction ANXA1-HS on angiogenesis strongly emerges. Moreover, once sequestered by HS, ANXA1 is not more able to bind the formil-peptide receptors (FPRs) preventing the increase of calcium mobilization, peculiar for cell motility. These findings introduce a new important tale in the knowledge about the inhibition of the ANXA1 action in PC development. Further information will be useful to highlight the interaction of HS with the protein, focusing on the characterization of the glycosaminoglycan and on in vivo assays. Copyright © 2020 Elsevier Inc. All rights reserved.

Citation

Raffaella Belvedere, Nunzia Novizio, Emanuela Pessolano, Alessandra Tosco, Daniela Eletto, Amalia Porta, Pietro Campiglia, Mauro Perretti, Amelia Filippelli, Antonello Petrella. Heparan sulfate binds the extracellular Annexin A1 and blocks its effects on pancreatic cancer cells. Biochemical pharmacology. 2020 Dec;182:114252