Research Papers:

Lactoferrin selectively triggers apoptosis in highly metastatic breast cancer cells through inhibition of plasmalemmal V-H+-ATPase

Cátia S. Pereira, Joana P. Guedes, Marília Gonçalves, Luís Loureiro, Lisandra Castro, Hernâni Gerós, Lígia R. Rodrigues and Manuela Côrte-Real _

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Oncotarget. 2016; 7:62144-62158. https://doi.org/10.18632/oncotarget.11394

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Cátia S. Pereira1,2, Joana P. Guedes1,2, Marília Gonçalves1, Luís Loureiro1, Lisandra Castro1, Hernâni Gerós1,3, Lígia R. Rodrigues2, Manuela Côrte-Real1

1Centre of Molecular and Environmental Biology (CBMA), Department of Biology, University of Minho, Braga, Portugal

2Centre of Biological Engineering (CEB), Department of Biological Engineering, University of Minho, Braga, Portugal

3Centre for the Research and Technology of Agro-Environmental and Biological Sciences (CITAB), Department of Biology, University of Minho, Braga, Portugal

Correspondence to:

Manuela Côrte-Real, email: [email protected]

Keywords: lactoferrin, V-H+-ATPase, breast cancer, V-H+-ATPase inhibitor, extracellular acidification rate

Received: December 09, 2015    Accepted: August 08, 2016    Published: August 19, 2016


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.

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