Native and iron-saturated bovine lactoferrin differently hinder migration in a model of human glioblastoma by reverting epithelial-to-mesenchymal transition-like process and inhibiting interleukin-6/STAT3 axis

Cutone, Antimo; Colella, Barbara; Pagliaro, Andrea; Rosa, Luigi; Lepanto, Maria Stefania; Patti, Maria Carmela Bonaccorsi di; Valenti, Piera; Bartolomeo, Sabrina Di; Musci, Giovanni

doi:10.1016/j.cellsig.2019.109461

Cited by 34 publications

(32 citation statements)

References 51 publications

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“…As expected, Lf showed selectivity by efficiently inhibiting migration and/or invasion in different types of cancer cell models [36,159,175,176]. Despite most of the studies do not detail the molecular mechanisms at the base of Lf anti-migratory and anti-invasive activities, two recent investigations have shed some light on bLf ability to revert epithelial-to-mesenchymal transition (EMT) process in both oral squamous cell carcinoma (OSCC) [176] and glioblastoma [36] cell lines. EMT is recognized as one of the main processes involved in cancer metastasis, where cells that gain a more invasive phenotype become able to infiltrate blood vessels as well as surrounding and distant tissues [177].…”

Section: Lactoferrin Anti-cancer Activity: Inhibition Of Cell Migratimentioning

confidence: 70%

“…Moreover, IL-6/STAT3 axis, another pivotal pathway associated to glioblastoma cell migration ability, was found to be strongly inhibited upon bLf treatment, with the holo-form more efficient than the native counterpart. Interestingly, the differential efficiency was associated to higher accumulation rates of holo-bLf in both cell cytoplasm and nucleus with respect to the native form [36]. A schematic representation of molecular mechanisms targeted by bLf for EMT reverting is shown in Figure 2.…”

Section: Lactoferrin Anti-cancer Activity: Inhibition Of Cell Migratimentioning

confidence: 99%

“…Some of the functions exerted by Lf can also be affected to its iron-binding status, as it is able to scavenge free iron in fluids and inflamed and/or infected sites, suppressing free radical-mediated damage and decreasing the availability of the metal to pathogens and cancer cells. In addition, many studies have shown that, depending on the iron-saturation rate, Lf can exert dissimilar functions by activating specific signaling pathways [35,36]. It is, therefore, of the utmost importance to consider the iron saturation rate when carrying out in vitro and in vivo experiments.…”

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confidence: 99%

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

et al. 2020

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Despite recent advances in cancer therapy, current treatments, including radiotherapy, chemotherapy, and immunotherapy, although beneficial, present attendant side effects and long-term sequelae, usually more or less affecting quality of life of the patients. Indeed, except for most of the immunotherapeutic agents, the complete lack of selectivity between normal and cancer cells for radioand chemotherapy can make them potential antagonists of the host anti-cancer self-defense over time. Recently, the use of nutraceuticals as natural compounds corroborating anti-cancer standard therapy is emerging as a promising tool for their relative abundance, bioavailability, safety, low-cost effectiveness, and immuno-compatibility with the host. In this review, we outlined the anti-cancer properties of Lactoferrin (Lf), an iron-binding glycoprotein of the innate immune defense. Lf shows high bioavailability after oral administration, high selectivity toward cancer cells, and a wide range of molecular targets controlling tumor proliferation, survival, migration, invasion, and metastasization. Of note, Lf is able to promote or inhibit cell proliferation and migration depending on whether it acts upon normal or cancerous cells, respectively. Importantly, Lf administration is highly tolerated and does not present significant adverse effects. Moreover, Lf can prevent development or inhibit cancer growth by boosting adaptive immune response. Finally, Lf was recently found to be an ideal carrier for chemotherapeutics, even for the treatment of brain tumors due to its ability to cross the blood-brain barrier, thus globally appearing as a promising tool for cancer prevention and treatment, especially in combination therapies.

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Section: Lactoferrin Anti-cancer Activity: Inhibition Of Cell Migratimentioning

confidence: 70%

Section: Lactoferrin Anti-cancer Activity: Inhibition Of Cell Migratimentioning

confidence: 99%

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confidence: 99%

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

et al. 2020

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“…IL-6 is an inflammatory factor widely reported to be involved in several pathological networks in cancer, and is also recognized as an activator of the STAT3 signalling pathway [ 11 , 12 ]. This pathway has been identified to be associated with invasive abilities, such as angiogenesis, chemotherapy resistance, and cell cycle progression [ 13 ].…”

Section: Introductionmentioning

confidence: 99%

Downregulation of RIPK4 Expression Inhibits Epithelial-Mesenchymal Transition in Ovarian Cancer through IL-6

Lin

et al. 2021

Journal of Immunology Research

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RIPK4 has been implicated in multiple cancer types, but its role in ovarian cancer (OC) has not been clearly elucidated. Our data from Gene Expression Profiling Interactive Analysis, RT-PCR, and immunohistochemical analysis showed that RIPK4 was expressed at higher levels in OC tissues and cells than in normal ovarian tissues and cells. Increased RIPK4 expression in OC markedly correlated with a worse overall survival than lower RIPK4 expression levels (hazard rate (HR) 1.5 (1.45–1.87); P = 0.001 ). In functional experiments, RIPK4 downregulation significantly inhibited metastatic behaviours in OC cells. Subsequently, based on data from 593 OC patients in the TCGA database, gene set enrichment analysis revealed that RIPK4 was involved in epithelial-mesenchymal transition (EMT) in OC. At the molecular level, silencing RIPK4 significantly downregulated vimentin, N-cadherin, and Twist expression but induced an increase in the protein level of E-cadherin and inhibited the IL-6 and STAT3 levels. Moreover, IL-6 levels were significantly decreased in RIPK4-silenced OC cells ( P < 0.05 ). The addition of IL-6 to OC cells rescued the suppressive effect of RIPK4 knockdown on EMT. Thus, our data illustrate that downregulation of RIPK4 expression can restrain EMT in OC by inhibiting IL-6. This finding may provide a novel diagnostic and therapeutic target for improving the poor prognoses of OC patients.

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“…Yang et al downstream signaling. 44,45 The decreased expression of IFN-β and IL-6 with allicin treatment suggested that allicin could inhibit HCMV activity and reduce the malignant degree of GBM. 46,47 Allicin also inhibited the expression of IL-6 and IFN-β in macrophages, which could inhibit the protumor features of M2 macrophages, as well as their differentiation.…”

Section: Dovepressmentioning

confidence: 99%

<p>Allicin Inhibits Proliferation by Decreasing IL-6 and IFN-β in HCMV-Infected Glioma Cells</p>

Yang

Zhu

et al. 2020

CMAR

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Allicin, an extract of garlic, has antitumor effects in multiple tumor types. However, the efficacy of allicin for treating glioblastoma has not yet been examined. This study examined the antitumor effect of allicin on human cytomegalovirus (HCMV)-infected glioblastoma multiforme (GBM) and its role in cytokine signaling. Materials and Methods: HCMV-infected glioblastoma was modeled by transfection of U87MG glioblastoma cells with HMCV proteins. MTT assay was used to assess the effect of allicin on the proliferation of glioma cells. Western blot analysis was used to detect the effect of allicin on the expression of intermediate-early gene 2 (IE2) and p53. Reverse transcription-quantitative polymerase chain reaction was used to assess and the levels of interleukin (IL)-6 and interferon (IFN)-β. Single cell gel electrophoresis was used to analyze changes in radiotherapy-induced DNA damage. Results: Transfection of the IE2 protein led to decreased p53 expression and increased glioblastoma cell proliferation. Allicin inhibited this proliferation in a dose-and time-dependent manner. An inhibitory effect on cytokine release was observed in GBM cells treated with allicin. After treatment with allicin, p53 levels increased significantly, whereas expression of the inflammatory factors such as IL-6 and IFN-β decreased. U87MG cells treated with allicin and 10 Gy irradiation had increased intracellular DNA damage compared to either treatment alone. Conclusion: Allicin inhibited proliferation of glioblastoma cells in vitro. Allicin also inhibited cytokine release, upregulated p53 activity, and increased the sensitivity of glioblastoma to radiotherapy. These results suggest that allicin is effective against HCMVinfected glioblastomas.

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Native and iron-saturated bovine lactoferrin differently hinder migration in a model of human glioblastoma by reverting epithelial-to-mesenchymal transition-like process and inhibiting interleukin-6/STAT3 axis

Cited by 34 publications

References 51 publications

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

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

Downregulation of RIPK4 Expression Inhibits Epithelial-Mesenchymal Transition in Ovarian Cancer through IL-6

<p>Allicin Inhibits Proliferation by Decreasing IL-6 and IFN-β in HCMV-Infected Glioma Cells</p>

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