Modulation of membrane properties of lung cancer cells by azurin enhances the sensitivity to EGFR-targeted therapy and decreased β1 integrin-mediated adhesion.
In lung cancer, the Epidermal Growth Factor Receptor (EGFR) is one of the main targets for clinical management of this disease. The effectiveness of therapies toward this receptor has already been linked to the expression of integrin receptor subunit β1 in NSCLC A549 cells. In this work we demonstrate that azurin, an anticancer therapeutic protein originated from bacterial cells, controls the levels of integrin β1 and its appropriate membrane localization, impairing the intracellular signaling cascades downstream these receptors and the invasiveness of cells. We show evidences that azurin when combined with gefitinib and erlotinib, tyrosine kinase inhibitors which targets specifically the EGFR, enhances the sensitivity of these lung cancer cells to these molecules. The broad effect of azurin at the cell surface level was examined by Atomic Force Microscopy. The Young 's module (E) shows that the stiffness of A549 lung cancer cells decreased with exposure to azurin and also gefitinib, suggesting that the alterations in the membrane properties may be the basis of the broad anticancer activity of this protein. Overall, these results show that azurin may be relevant as an adjuvant to improve the effects of other anticancer agents already in clinical use, to which patients often develop resistance hampering its full therapeutic response.
a iBB-Institute for Bioengineering and Biosciences, Biological Sciences Research Group , Lisbon , Portugal.
Nuno
N
Bernardes
a iBB-Institute for Bioengineering and Biosciences, Biological Sciences Research Group , Lisbon , Portugal.
Sofia
S
Abreu
b Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa , Lisbon , Portugal.
Filomena A
FA
Carvalho
c Centro de Quimica-Fisica Molecular, Instituto Superior Técnico , Lisbon , Portugal.
Fábio
F
Fernandes
b Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa , Lisbon , Portugal.
Nuno C
NC
Santos
a iBB-Institute for Bioengineering and Biosciences, Biological Sciences Research Group , Lisbon , Portugal.|d Department of Bioengineering , Instituto Superior Técnico, University of Lisbon , Lisbon , Portugal.
Arsénio M
AM
Fialho
D000072283:A549 Cells; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001400:Azurin / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000494:pharmacology; D002448:Cell Adhesion / Q000187:drug effects; D002462:Cell Membrane / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004357:Drug Synergism; D055119:Elastic Modulus; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D000069347:Erlotinib Hydrochloride / Q000494:pharmacology*; D005109:Extracellular Matrix / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D000077156:Gefitinib; D015870:Gene Expression; D006801:Humans; D019012:Integrin beta1 / Q000235:genetics* / Q000378:metabolism; D018625:Microscopy, Atomic Force; D011799:Quinazolines / Q000494:pharmacology*; D013499:Surface Properties
D000970:Antineoplastic Agents; D001426:Bacterial Proteins; D019012:Integrin beta1; D011799:Quinazolines; D001400:Azurin; D000069347:Erlotinib Hydrochloride; C512478:EGFR protein, human; D066246:ErbB Receptors; D000077156:Gefitinib
EGFR; NSCLC; atomic force microscoy; azurin; gefitinib; integrin; β1