Iron-free and iron-saturated bovine lactoferrin inhibit survivin expression and differentially modulate apoptosis in breast cancer

Jessica A. Gibbons, Jagat R. Kanwar, Rupinder K. Kanwar

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35 Citations (Scopus)

Abstract

Iron binding, naturally occurring protein bovine lactoferrin (bLf) has attracted attention as a safe anti-cancer agent capable of inducing apoptosis. Naturally, bLf exists partially saturated (15-20%) with Fe3+ however, it has been demonstrated that manipulating the saturation state can enhance bLf's anti-cancer activities. Methods: Apo-bLf (Fe3+ free) and Fe-bLf (>90% Fe3+ Saturated) were therefore, tested in MDA-MB-231 and MCF-7 human breast cancer cells in terms of cytotoxicity, proliferation, migration and invasion. Annexin-V Fluos staining was also employed in addition to apoptotic protein arrays and Western blotting to determine the specific mechanism of bLf-induced apoptosis with a key focus on p53 and inhibitor of apoptosis proteins (IAP), specifically survivin. Results: Apo-bLf induced significantly greater cytotoxicity and reduction in cell proliferation in both cancer cells showing a time and dose dependent effect. Importantly, no cytotoxicity was detected in normal MCF-10-2A cells. Both forms of bLf significantly reduced cell invasion in cancer cells. Key apoptotic molecules including p53, Bcl-2 family proteins, IAP members and their inhibitors were significantly modulated by both forms of bLf, though differentially in each cell line. Most interestingly, both Apo-bLf and Fe-bLf completely inhibited the expression of survivin protein (key IAP), after 48h at 30 and 40 nM in cancer cells. Conclusions: The capacity of these forms of bLf to target survivin expression and modulation of apoptosis demonstrates an exciting potential for bLf as an anti-cancer therapeutic in the existing void of survivin inhibitors, with a lack of successful inhibitors in the clinical management of cancer.

Original languageEnglish
Article number425
Number of pages16
JournalBMC Cancer
Volume15
DOIs
Publication statusPublished - 22 May 2015
Externally publishedYes

Keywords

  • Apoptosis
  • Bovine lactoferrin (bLf)
  • Breast cancer
  • Invasion
  • p53
  • Survivin

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