Neutrophil lactoferrin upregulates the human p53 gene through induction of NF-κB activation cascade

Oh, Sang Muk; Pyo, Chul Woong; Kim, Young‐Ho; Choi, Seo‐Hyun

doi:10.1038/sj.onc.1208021

Cited by 58 publications

(46 citation statements)

References 30 publications

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“…Our data, as well as that of Oh, confirm that lactoferrin up-regulates NF-nB in cancer cell lines (39). It is possible that the effects of lactoferrin on NF-nB activity may differ based upon the cell type (monocytes versus carcinoma cell lines), and it seems from our results that the lactoferrin effect on NF-nB is not directly causative of growth inhibition.…”

Section: Discussionsupporting

confidence: 86%

Oral Lactoferrin Results in T Cell–Dependent Tumor Inhibition of Head and Neck Squamous Cell Carcinoma In vivo

Wolf¹,

Li²,

Varadhachary³

et al. 2007

Clinical Cancer Research

103

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Purpose: Human lactoferrin is a naturally occurring glycoprotein that inhibits cancer growth. Our purpose was to evaluate recombinant human lactoferrin as a chemotherapeutic agent against head and neck squamous cell carcinoma. Experimental Design: Controlled experiments both in vitro and in the murine model evaluating both the effect and mechanism of lactoferrin on cancer growth. Results: In both human and murine cell lines, lactoferrin induced dose-dependent growth inhibition. Using flow cytometric analysis, lactoferrin was shown to induce G 1 -G 0 growth arrest. This arrest seemed to be modulated by down-regulation of cyclin D1. In the in vitro model, luminex data revealed that lactoferrin inhibited cellular release of proinflammatory and prometastatic cytokines, including interleukin-8, interleukin-6, granulocyte macrophage colony-stimulating factor, and tumor necrosis factor-a. Lactoferrin up-regulated the cellular activation of nuclear factor-nB within 4 h of cellular exposure. In C3h/HeJ mice implanted with SCCVII tumors, orally delivered lactoferrin inhibited tumor growth by 75% compared with control mice. Immunohistochemical analysis of harvested tumors revealed up to 20-fold increases of lymphocytes within treated animals. When mice were depleted of CD3 + cells, all lactoferrin-induced tumor inhibition was abrogated. Conclusion: We conclude that human recombinant lactoferrin can inhibit the growth of head and neck squamous cell carcinoma via direct cellular inhibition as well as systemically via immunomodulation. Our data support the study of human lactoferrin as an immunomodulatory compound with therapeutic potential.

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Section: Discussionsupporting

confidence: 86%

Oral Lactoferrin Results in T Cell–Dependent Tumor Inhibition of Head and Neck Squamous Cell Carcinoma In vivo

Wolf¹,

Li²,

Varadhachary³

et al. 2007

Clinical Cancer Research

103

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“…Interestingly, a small portion of the LF was found in the crude nuclear extract fraction of the cells by Western blotting. LF was reported to possess nuclear function by acting as a gene transcription factor by binding to specific DNA sequences [52] or interfering with cellular events leading to NF-κB activation or suppression [53,54]. It is not clear whether LF in the HC-11 cells entered the nucleus and suppressed proinflammatory cytokine production by interfering with NF-κB activation after LPS exposure.…”

Section: Discussionmentioning

confidence: 99%

Induction of lactoferrin gene expression by innate immune stimuli in mouse mammary epithelial HC-11 cells

Limmon

Imani

et al. 2009

Biochimie

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Lactoferrin (LF) is a multifunctional protein. While its functions and mechanism of actions are actively being investigated, the cellular signals that regulate LF expression have not been as explored. We have previously demonstrated that LF is upregulated by estrogen in reproductive system. In this study, we show that the expression of LF was stimulated by bacterial lipopolysaccharide (LPS) and double-stranded RNA (dsRNA) in normal mouse mammalian HC-11 cells. When cells were exposed to either LPS or dsRNA, the mRNA and protein of LF were increased in a dose-and time-dependent manner, yet the kinetics of LF induction by dsRNA or LPS was different. The LPS and dsRNAinduced LF was mainly released into the culture medium where it blocked TNF-α production in exposed cells. We explored the mechanisms of LF induction by LPS and dsRNA using specific inhibitors and found that the induction could be attenuated by inhibitors to PKC, NF-kB, p38 and JNK, but not by an inhibitor to PKA. Interestingly, ERK inhibitor was effective against dsRNA but not against LPS induction of LF. These data suggest that LF was induced by LPS and dsRNA through PKC, NF-kB and MAPK pathways which in turn plays an inhibitory role in the continuation of innate inflammation.

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“…We demonstrated previously that Lf induces the phosphorylation and subsequent degradation of IB molecules via the MEKK1-IKK signaling cascades (21). In this study, we attempted to investigate which cellular components were most closely associated with the role of Lf as a signal transducer, leading to the activation of the p65 NF-B subunit.…”

Section: A Distinct Role Of Neutrophil Lactoferrin Inmentioning

confidence: 99%

“…Plasmids pRK-Flag-IKK␣, pRK-Flag-IKK␤, pRK-Flag-IKK␣ (K44A), pRKFlag-IKK␤ (K44A), and pRK-Flag-NIK (KK429 -430AA) were described previously (21). Plasmid GAL4-p65 (1-551) expressing the DNA-binding domain of yeast GAL4 protein fused to the p65 was generated via the cloning of the PCR product into the EcoRI/XbaI sites of the pM vector (BD Clontech).…”

Section: Plasmids and Small Interfering Rnas (Sirnas)mentioning

confidence: 99%

A Distinct Role of Neutrophil Lactoferrin in RelA/p65 Phosphorylation on Ser536 by Recruiting TNF Receptor-Associated Factors to IκB Kinase Signaling Complex

Lee

et al. 2007

The Journal of Immunology

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The activation of NF-κB by neutrophil lactoferrin (Lf) is regulated via the IκB kinase (IKK) signaling cascade, resulting in the sequential phosphorylation and degradation of IκB. In this study, we observed that Lf protein augmented p65 phosphorylation at the Ser536, but not the Ser276 residue, and stimulated the translocation of p65 into the nucleus. Lf was also shown to enhance the association between p65 and CREB-binding protein/p300 in vivo. To elucidate the mechanism by which Lf triggers these signaling pathways, we attempted to delineate the roles of the upstream components of the IKK complex, using their dominant-negative mutants and IKKα−/− and IKKβ−/− mouse embryonic cells. We demonstrated that both IKKα and IKKβ as well as NF-κB-inducing kinase are indispensable for Lf-induced p65 phosphorylation. However, MAPK kinase kinase 1 is not essentially required for this activation. We also observed that Lf-induced p65 phosphorylation was either partially or completely abrogated as the result of treatment with the mutant forms of TNFR-associated factor (TRAF) 2, TRAF5, or TRAF6. Moreover, we demonstrated that Lf directly interacted with TRAF5. Expression of the dominant-negative mutant of TRAF5 or its small interfering RNA almost completely abrogated the Lf-induced p65 phosphorylation. These results suggest that signaling pathways, including TRAFs/NF-κB-inducing kinase/IKKs, may be involved in the regulation of Lf-induced p65 activation, thereby resulting in the activation of members of the NF-κB family.

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Neutrophil lactoferrin upregulates the human p53 gene through induction of NF-κB activation cascade

Cited by 58 publications

References 30 publications

Oral Lactoferrin Results in T Cell–Dependent Tumor Inhibition of Head and Neck Squamous Cell Carcinoma In vivo

Oral Lactoferrin Results in T Cell–Dependent Tumor Inhibition of Head and Neck Squamous Cell Carcinoma In vivo

Induction of lactoferrin gene expression by innate immune stimuli in mouse mammary epithelial HC-11 cells

A Distinct Role of Neutrophil Lactoferrin in RelA/p65 Phosphorylation on Ser536 by Recruiting TNF Receptor-Associated Factors to IκB Kinase Signaling Complex

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