Lactoferrin perturbs intracellular trafficking, disrupts cholesterol-rich lipid rafts and inhibits glycolysis of highly metastatic cancer cells harbouring plasmalemmal V-ATPase
The milk-derived bovine lactoferrin (bLf) is an iron-binding glycoprotein with remarkable selective anticancer activity towards highly metastatic cancer cells displaying the proton pump V-ATPase at the plasma membrane. As studies aiming to dissect the bLf mechanisms of action are critical to improve...
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| Published in: | International journal of biological macromolecules Vol. 220; pp. 1589 - 1604 |
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| Main Authors: | , , , , |
| Format: | Journal Article |
| Language: | English |
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Elsevier B.V
01-11-2022
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| Abstract | The milk-derived bovine lactoferrin (bLf) is an iron-binding glycoprotein with remarkable selective anticancer activity towards highly metastatic cancer cells displaying the proton pump V-ATPase at the plasma membrane. As studies aiming to dissect the bLf mechanisms of action are critical to improve its efficacy and boost its targeted clinical use, herein we sought to further uncover the molecular basis of bLf anticancer activity. We showed that bLf co-localizes with V-ATPase and cholesterol-rich lipid rafts at the plasma membrane of highly metastatic cancer cells. Our data also revealed that bLf perturbs cellular trafficking, induces intracellular accumulation of cholesterol and lipid rafts disruption, downregulates PI3K, and AKT or p-AKT and inhibits glycolysis of cancer cells harbouring V-ATPase at the plasma membrane lipid rafts. Altogether, our results can lay the foundation for future bLf-based targeted anticancer strategies as they unravel a novel cascade of molecular events that explains and further reinforces bLf selectivity for cancer cells displaying plasmalemmal V-ATPase.
•Lactoferrin perturbs intracellular trafficking and inhibits glycolysis.•Lactoferrin disrupts cholesterol-rich lipid rafts of highly metastatic cancer cells.•A novel cascade of molecular events triggered by lactoferrin in cancer cells was unveiled. |
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| AbstractList | The milk-derived bovine lactoferrin (bLf) is an iron-binding glycoprotein with remarkable selective anticancer activity towards highly metastatic cancer cells displaying the proton pump V-ATPase at the plasma membrane. As studies aiming to dissect the bLf mechanisms of action are critical to improve its efficacy and boost its targeted clinical use, herein we sought to further uncover the molecular basis of bLf anticancer activity. We showed that bLf co-localizes with V-ATPase and cholesterol-rich lipid rafts at the plasma membrane of highly metastatic cancer cells. Our data also revealed that bLf perturbs cellular trafficking, induces intracellular accumulation of cholesterol and lipid rafts disruption, downregulates PI3K, and AKT or p-AKT and inhibits glycolysis of cancer cells harbouring V-ATPase at the plasma membrane lipid rafts. Altogether, our results can lay the foundation for future bLf-based targeted anticancer strategies as they unravel a novel cascade of molecular events that explains and further reinforces bLf selectivity for cancer cells displaying plasmalemmal V-ATPase.
•Lactoferrin perturbs intracellular trafficking and inhibits glycolysis.•Lactoferrin disrupts cholesterol-rich lipid rafts of highly metastatic cancer cells.•A novel cascade of molecular events triggered by lactoferrin in cancer cells was unveiled. |
| Author | Guedes, Joana P. Côrte-Real, Manuela Rodrigues, Lígia R. Ferreira, Débora Santos-Pereira, Cátia |
| Author_xml | – sequence: 1 givenname: Cátia surname: Santos-Pereira fullname: Santos-Pereira, Cátia organization: Centre of Molecular and Environmental Biology (CBMA), Department of Biology, University of Minho, 4710-057 Braga, Portugal – sequence: 2 givenname: Joana P. surname: Guedes fullname: Guedes, Joana P. organization: Centre of Molecular and Environmental Biology (CBMA), Department of Biology, University of Minho, 4710-057 Braga, Portugal – sequence: 3 givenname: Débora surname: Ferreira fullname: Ferreira, Débora organization: Centre of Biological Engineering (CEB), Department of Biological Engineering, University of Minho, 4710-057 Braga, Portugal – sequence: 4 givenname: Lígia R. surname: Rodrigues fullname: Rodrigues, Lígia R. organization: Centre of Biological Engineering (CEB), Department of Biological Engineering, University of Minho, 4710-057 Braga, Portugal – sequence: 5 givenname: Manuela surname: Côrte-Real fullname: Côrte-Real, Manuela email: mcortereal@bio.uminho.pt organization: Centre of Molecular and Environmental Biology (CBMA), Department of Biology, University of Minho, 4710-057 Braga, Portugal |
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| CitedBy_id | crossref_primary_10_1002_fsn3_4020 crossref_primary_10_1016_j_jenvman_2023_118114 crossref_primary_10_3390_jcm12175546 crossref_primary_10_3390_pharmaceutics15082162 |
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