Author(s):
Pereira, Cátia S. ; Guedes, J. ; Gonçalves, Marília ; Loureiro, Luís ; Castro, Lisandra ; Gerós, Hernâni ; Rodrigues, L. R. ; Côrte-Real, Manuela
Date: 2016
Persistent ID: http://hdl.handle.net/1822/42765
Origin: RepositóriUM - Universidade do Minho
Project/scholarship:
info:eu-repo/grantAgreement/FCT/5876/147364/PT;
info:eu-repo/grantAgreement/FCT/5876/147337/PT;
info:eu-repo/grantAgreement/FCT/5876-PPCDTI/126270/PT
;
info:eu-repo/grantAgreement/FCT/COMPETE/126270/PT;
info:eu-repo/grantAgreement/FCT/3599-PPCDT/125757/PT
;
Subject(s): Lactoferrin; V-H+-ATPase; breast cancer; V-H+-ATPase inhibitor; extracellular acidification rate; Science & Technology
Description
Breast cancer is the most common type of cancer affecting women. Despite the good prognosis when detected early, significant challenges remain in the treatment of metastatic breast cancer. The recruitment of the vacuolar H+-ATPase (V-H+-ATPase) to the plasma membrane, where it mediates the acidification of the tumor microenvironment (TME), is a recognized feature involved in the acquisition of a metastatic phenotype in breast cancer. Therefore, inhibitors of this pump have emerged as promising anticancer drugs. Lactoferrin (Lf) is a natural pro-apoptotic iron-binding glycoprotein with strong anticancer activity whose mechanism of action is not fully understood. Here, we show that bovine Lf (bLf) preferentially induces apoptosis in the highly metastatic breast cancer cell lines Hs 578T and MDA-MB-231, which display a prominent localisation of V-H+-ATPase at the plasma membrane, but not in the lowly metastatic T-47D or in the non-tumorigenic MCF-10-2A cell lines. We also demonstrate that bLf decreases the extracellular acidification rate and causes intracellular acidification in metastatic breast cancer cells and, much like the well-known proton pump inhibitors concanamycin A and bafilomycin A1, inhibits V-H+-ATPase in sub-cellular fractions. These data further support that bLf targets V-H+-ATPase and explain the selectivity of bLf for cancer cells, especially for highly metastatic breast cancer cells. Altogether, our results pave the way for more rational in vivo studies aiming to explore this natural non-toxic compound for metastatic breast cancer therapy.
This study was supported by national funds through FCT I.P and the European Community fund ERDF, through Program COMPETE2020 - Programa Operacional Competitividade e Internacionalização (POCI), under the scope of the strategic programmes UID/BIA/04050/2013 (POCI-01-0145-FEDER-007569) and UID/BIO/04469/2013; by the Programa Operacional Regional do Norte (ON.2 – O Novo Norte), QREN, ERDF through project RECI/BBB EBI/0179/2012 (FCOMP-01-0124-FEDER-027462); as well as by FCT through the program PIDDAC (project FCT-ANR/ BEX-BCM/0175/2012).
