Molecular mechanism of inhibitory effects of bovine lactoferrin on the growth of oral squamous cell carcinoma

Abstract

BackgroundLactoferrin (LF), a member of the transferrin family, recently has been demonstrated to have anticancer effects on various cancers including oral squamous cell carcinoma (OSCC). However, little is known about the underlying mechanisms of its effects on OSCC. Therefore, we aimed to investigate the mechanism of the suppressive effects of bovine LF (bLF) on the growth of OSCC cells.MethodsIn the current study, HSC2, HSC3, HSC4 and normal human oral keratinocytes (RT7) cell lines were tested with bLF 1, 10, and 100 μg/ml. The effects and detail mechanisms of bLF on proliferation and apoptosis of cells were investigated using flow cytometry and western blotting.ResultsWe found that bLF (1, 10, and 100 μg/ml) induced activation of p53, a tumor suppressor gene, is associated with the induction of cell cycle arrest in G1/S phase and apoptosis in OSCC. Moreover, bLF downregulated the phosphorylation of Akt and activated suppressor of cytokine signaling 3 (SOCS3), thereby attenuating multiple signaling pathways including mTOR/S6K and JAK/STAT3. Interestingly, we revealed that bLF exerted its effect selectively against HSC3 but not on RT7 via different effects on the phosphorylation status of NF-κB and Akt.ConclusionThis is the first report showing that bLF selectively suppresses proliferation through mTOR/S6K and JAK/STAT3 pathways and induction of apoptosis in OSCC. This study provides important new findings, which might be useful in the prevention and treatment of OSCC.

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“…Compared with the control, the proportion of cells at G2/M phase increased in both free bLF and its conjugated form; but, the effect of CGO-PEG-bLF in arresting the cells was significantly higher than that of free bLF. Despite our results, several reports have demonstrated that bLF arrested the cell cycle in the G1/S phase in some types of cancers (Zhou et al., 2008 ; Xu et al., 2010 ; Chea et al., 2018 ). Induction of cell cycle arrest at the G2/M phase in MDA-MB-231 and T-47D cells has been reported by Zhang et al.…”

“…Although, other proteins may be involved in this process. Similar results regarding effect of bLF on the three cell lines of oral squamous cell carcinoma (HSC1, HSC2, HSC3) have been reported by Chea et al (Chea et al., 2018 ). Their findings indicated that bLF downregulated the phosphorylation of AKT and upregulated the cleaved-caspase 3 protein selectively in HSC3 cells but not in RT7 (normal human oral keratinocytes).…”

“…The induction of apoptosis by bLF was reported in several studies. This effect was mainly dependent on the cell type, dose of treatment, and time of the experiment and involved with different signaling pathways (Zhang et al., 2014 ; Chea et al., 2018 ; Guedes et al., 2018 ).…”

Lactoferrin’s Anti-Cancer Properties: Safety, Selectivity, and Wide Range of Action

“…In line with these studies, Chea et al [145] showed that bLf was able to induce cell cycle arrest also in a model of oral squamous cell carcinoma by increasing levels of both phospho-p53 and CdK inhibitor p21 and decreasing the expression of cyclin D1, a regulator protein required for progression through G1 phase of cell cycle. Importantly, bLf neither down-regulated phospho-p53 and cyclin D1 nor up-regulated p21 levels in RT7 cells, a normal human oral keratinocytes line [145].…”

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“… [ 69 ] OSCC bLf Selective suppression of growth through mTOR/S6K & JAK/STAT3 signaling pathways and triggering of apoptosis in OSCC. [ 70 ] Head & Neck Recombinant hLf LF induced growth inhibitory effects via p27/cyclin E-dependent signaling pathway by regulating Akt phosphorylation. [ 71 ] GBM hLf Suppression of the proliferation of NMD and FN primary cells as well as U87MG cells by reducing the expression of cyclin D1 and D4.…”