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

Research output: Contribution to journalArticleResearchpeer-review

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

Cite this

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title = "Iron-free and iron-saturated bovine lactoferrin inhibit survivin expression and differentially modulate apoptosis in breast cancer",
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.",
keywords = "Apoptosis, Bovine lactoferrin (bLf), Breast cancer, Invasion, p53, Survivin",
author = "Gibbons, {Jessica A.} and Kanwar, {Jagat R.} and Kanwar, {Rupinder K.}",
year = "2015",
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Iron-free and iron-saturated bovine lactoferrin inhibit survivin expression and differentially modulate apoptosis in breast cancer. / Gibbons, Jessica A.; Kanwar, Jagat R.; Kanwar, Rupinder K.

In: BMC Cancer, Vol. 15, 425, 22.05.2015.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Iron-free and iron-saturated bovine lactoferrin inhibit survivin expression and differentially modulate apoptosis in breast cancer

AU - Gibbons, Jessica A.

AU - Kanwar, Jagat R.

AU - Kanwar, Rupinder K.

PY - 2015/5/22

Y1 - 2015/5/22

N2 - 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.

AB - 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.

KW - Apoptosis

KW - Bovine lactoferrin (bLf)

KW - Breast cancer

KW - Invasion

KW - p53

KW - Survivin

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U2 - 10.1186/s12885-015-1441-4

DO - 10.1186/s12885-015-1441-4

M3 - Article

VL - 15

JO - BMC Cancer

JF - BMC Cancer

SN - 1471-2407

M1 - 425

ER -