A review on lactoferrin as a proton pump inhibitor

Highlights

• Lactoferrin inhibits bacterial F-ATPase contributing to its antimicrobial activity.

• Lactoferrin hinders both Pma1p and V-ATPase of yeast cells deregulating pH.

• Lactoferrin selectively impairs V-ATPase activity of highly metastatic cancer cells.

• Repurposing of proton pump inhibitors towards anticancer therapy is promising.

Abstract

Lactoferrin (Lf) is a versatile natural milk-derived protein that exhibits multiple interesting biological activities. Since it is safe for human administration and currently manufactured using low cost and well-established large-scale processes, the Lf scientific community has been devoted at dissecting its mechanisms of action towards its more rational and efficient use for various applications. Emerging literature has identified proton pumping ATPases as molecular targets of Lf in different cellular models linked to distinct activities of this natural protein. Information on this subject has not been systematically analysed before, hence herein we review the current state of art on the effect of Lf on proton pumping ATPases. Though structurally different, we propose that Lf holds a proton pump inhibitor (PPI)-like activity based on the functional resemblance with the classical inhibitors of the stomach H⁺/K⁺-ATPase. The downstream events and outcomes of the PPI-like activity of Lf, as well as its impact for the development of improved Lf applications are also discussed.

https://doi.org/10.1016/j.ijbiomac.2022.01.075

Lactoferrin perturbs intracellular trafficking, disrupts cholesterol-rich lipid rafts and inhibits glycolysis of highly metastatic cancer cells harbouring plasmalemmal V-ATPase

Highlights

• 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.

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.

https://doi.org/10.1016/j.ijbiomac.2022.09.120

Plasmalemmal V-ATPase as a Potential Biomarker for Lactoferrin-Based Anticancer Therapy

Abstract

Lactoferrin (Lf) is a milk-derived protein with well-recognized potential as a therapeutic agent against a wide variety of cancers. This natural protein exhibits health-promoting effects and has several interesting features, including its selectivity towards cancer cells, good tolerability in humans, worldwide availability, and holding a generally recognized as safe (GRAS) status. To prompt the rational clinical application of this promising anticancer compound, previous works aimed to unveil the molecular mechanisms underlying its selective anticancer activity, where plasmalemmal V-ATPase was identified as an Lf target in cancer cells. V-ATPase is a proton pump critical for cellular homeostasis that migrates to the plasma membrane of highly metastatic cancer cells contributing to the acidity of the tumor microenvironment. Cancer cells were found to be susceptible to Lf only when this proton pump is present at the plasma membrane. Plasmalemmal V-ATPase can thus be an excellent biomarker for driving treatment decisions and forecasting clinical outcomes of Lf-based anticancer strategies. Future research endeavors should thus seek to validate this biomarker by thorough preclinical and clinical studies, as well as to develop effective methods for its detection under clinical settings.

https://doi.org/10.3390/biom12010119

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

Antifungal Mechanism of Action of Lactoferrin: Identification of V-ATPase as a New Apoptotic-Cell Membrane Receptor

The milk-derived lactoferrin inhibits V-ATPase activity by targeting its V1 domain

How can a milk protein selectively kill cancer cells? Mechanisms underlying lactoferrin-induced apoptosis