Molecular Mechanisms of Inhibitory Effects of Bovine Lactoferrin on Invasion of Oral Squamous Cell Carcinoma

Abstract

Lactoferrin (LF), an iron-binding glycoprotein, has been reported to have anticancer properties. However, the molecular mechanisms behind its anticancer effects on oral squamous cell carcinoma (OSCC) have not yet been elucidated. Therefore, we aimed to clarify the effects of LF on invasion of OSCC, and its underlying molecular mechanism. OSCC cell lines, HSC2 and HOC313, were treated with bovine LF (bLF). The effects of bLF on cell invasion were examined by a chamber migration assay, wound healing assay, and Boyden chamber method with a basement-membrane-analogue. Expression levels of MMP-1, MMP-3, and AP-1 were examined using RT-PCR, qRT-PCR, and western blotting. Roles of LRP1, a receptor of bLF, on cell invasion were analyzed using siLRP1 knockdown cells. Furthermore, to clarify the importance of LRP1 in invasion, the effects of bLF on tPA-induced invasion of OSCC cells were examined. The invasion assays showed that bLF suppressed invasion of the OSCC cells. Moreover, bLF down-regulated AP-1, and resulted in reductions of MMP-1 and MMP-3. With SiLRP1 knockdown, OSCC cells failed to induce their invasion, and bLF was not able to exert its effects on invasion. Furthermore, bLF remarkably inhibited tPA-induced cell invasion. These findings suggest the importance of LRP1 in bLF-suppressed invasion of OSCC cells via the reduction of AP-1 and MMP production.

The anticancer activity of bovine lactoferrin is reduced by deglycosylation and it follows a different pathway in cervix and colon cancer cells

“…LfR was identified as a specific receptor of human LF that associates with AP2, which mediates internalization via clathrin endocytosis to stimulate ERK signaling (Jiang et al., 2011 ). The low‐density lipoprotein receptor‐related protein (LRP‐1) is a major endocytic receptor known to bind more than 35 ligands with signaling properties (Etique et al., 2013 ), and different evidences suggest that LRP‐1 could be a likely bLF receptor in different models (Chea et al., 2023 ; Takayama et al., 2003 ). After binding to LRP‐1, bLF promoted the phosphorylation of Akt1 and extracellular signal‐regulated protein kinase (ERK1/2); an induction process that requires iron‐saturated bLF (holo‐LF) (Ryu et al., 2017 ).…”

Lysyl oxidase-like 4 promotes the invasiveness of triple-negative breast cancer cells by orchestrating the invasive machinery formed by annexin A2 and S100A11 on the cell surface

“…It has been reported that the milk protein lactoferrin works to prevent cancer progression through iron chelation by competing with transferrin, which is in the same family of proteins ( 41 , 42 ). Owing to the solid inhibitory power of lactoferrin against plasmin ( 43 , 44 ), its cancer prevention effect may be ascribed to both chelation of iron (a vital cancer nutrient) and inhibition of plasmin. These results emphasize that cell surface plasmin is a potent druggable target for the prevention of life-threatening cancer metastasis.…”

Lactoferricin B Combined with Antibiotics Exhibits Leukemic Selectivity and Antimicrobial Activity

“…To investigate the anticancer efficacy of a PP other than CPPs (TP10 and NHP) combined with antibiotics, we selected lactoffericin B (LfcinB), an AMP with established anticancer activity and low toxicity [47][48][49][50][51][52][53][54]. LfcinB is a shorter version of lactoferrin, and like the original peptide, it demonstrates anticancer properties [55][56][57][58][59][60][61][62].…”