Lactoferrin as a Human Genome "Guardian"-An Overall Point of View

Abstract

Structural abnormalities causing DNA modifications of the ethene and propanoadducts can lead to mutations and permanent damage to human genetic material. Such changes may cause premature aging and cell degeneration and death as well as severe impairment of tissue and organ function. This may lead to the development of various diseases, including cancer. In response to a damage, cells have developed defense mechanisms aimed at preventing disease and repairing damaged genetic material or diverting it into apoptosis. All of the mechanisms described above are part of the repertoire of action of Lactoferrin-an endogenous protein that contains iron in its structure, which gives it numerous antibacterial, antiviral, antifungal and anticancer properties. The aim of the article is to synthetically present the new and innovative role of lactoferrin in the protection of human genetic material against internal and external damage, described by the modulation mechanisms of the cell cycle at all its levels and the mechanisms of its repair.

Keywords: DNA damage; DNA glycosylases; lactoferrin; oxidative stress.

Figure 1

DNA damaging internal and external factors causing formation of etheno and propano base derivatives.

Figure 2

Major factors causing DNA damage and the protective effects of lactoferrin. Factors of external and internal origin as well as bacterial and viral infections can lead to mutations and permanent damage to human genetic material, causing premature aging and cell death, as well as severe impairment of the functions of tissues and organs, which in turn may lead to the development of various diseases, including cancer. In response to these carnivores, cells have developed defense mechanisms to prevent disease and repair damaged genetic material in the form of equal repair systems, such as BER or NER, or by diverting the cell to apoptosis. The protein supporting these mechanisms is Lactoferrin—an endogenous protein which, due to its unique structure, has numerous antibacterial, antiviral, antifungal and anticancer properties. These properties help to bind to damaged (modified) DNA, which supports the functioning of the mechanisms modulating the cell cycle at all its levels and the mechanisms of its repair. Illustration was created in BioRender.com (accessed on 21 April 2022).

Figure 3

Lactoferrin direct action. LF acts as a multipotent protective factor both by acting on DNA, activating transcription factors, gene expression, regulating the cell cycle, differentiation and leading to the death of cells that threaten the body, such as cancer cells.

Figure 4

Protective role of LF against mitochondrial damage. Mitochondrial damage is a phenomenon that occurs in various diseases. LF can protect mitochondria by multiple mechanisms, acting as an antipathogenic agent and activating immune cell responses.

Figure 5

Modulation of cell cycle by bLF and rhLF demonstrated on the example of different cancer cells lines. During the cell cycle, LF can inhibit or activate several checkpoint regulators such as: cyclin-dependent kinase (CDK), and their associated inhibitor partners of the Cip/Kip family proteins (p21, p27), DNA damage response genes (p53) or mTOR/S6K pathway. In response to bLF and rhLF cancer target cells arrest in G₀/G₁ phase (e.g., HSC3 cells, head and neck cancer line), G₁/G₂ phase (e.g., OSCC, MDA-MD-231 cells, nasopharyngeal carcinoma cells), G2/M phase (e.g., ALL cells) or S phase (e.g., MDA-MB-231 cells, A549 cells). Key molecules that lead to cell cycle arrest are indicated by the red arrows. Illustration was created in BioRender.com (accessed on 21 April 2022).

Figure 6

Overview of the mechanism underlying the apoptotic activity of bLF including activation of Fas signaling pathway in MDA-MB-231 cells (A), mitochondrial-related pathway in MCF-7 cells (B) and inhibition of plasmalemmal V-H+-ATPase proton pumping of highly metastatic cancer cells (V-ATPase), bacteria (F-ATPase) as well as yeast (Pma1p). (A,B) The internalized, Apo-bLF and Fe-bLF via membrane bound LF receptors in the process of endocytosis, induce or/and inhibit key apoptotic proteins. (C) The inhibition of proton efflux trigger extracellular alkalinisation and intracellular acidification. Modulation of key apoptotic molecules level or processes that lead to cell death are indicated by the red arrows. pH_i: intracellular pH; pH_lys: lysosomal pH; pH_vac: vacuolar pH; [ATP]_i: intracellular ATP concentration; ψ_pm: plasma membrane potential. Illustration was created in BioRender.com (accessed on 21 April 2022) based on [110,184].