Temporal Quantitative Proteomics Analysis of Neuroblastoma Cells Treated with Bovine Milk-Derived Extracellular Vesicles Highlights the Anti-Proliferative Properties of Milk-Derived Extracellular Vesicles

Abstract

Neuroblastoma (NBL) is a pediatric cancer that accounts for 15% of childhood cancer mortality. Amplification of the oncogene N-Myc occurs in 20% of NBL patients and is considered high risk as it correlates with aggressiveness, treatment resistance and poor prognosis. Even though the treatment strategies have improved in the recent years, the survival rate of high-risk NBL patients remain poor. Hence, it is crucial to explore new therapeutic avenues to sensitise NBL. Recently, bovine milk-derived extracellular vesicles (MEVs) have been proposed to contain anti-cancer properties. However, the impact of MEVs on NBL cells is not understood. In this study, we characterised MEVs using Western blotting, NTA and TEM. Importantly, treatment of NBL cells with MEVs decreased the proliferation and increased the sensitivity of NBL cells to doxorubicin. Temporal label-free quantitative proteomics of NBL cells highlighted the depletion of proteins involved in cell metabolism, cell growth and Wnt signalling upon treatment with MEVs. Furthermore, proteins implicated in cellular senescence and apoptosis were enriched in NBL cells treated with MEVs. For the first time, this study highlights the temporal proteomic profile that occurs in cancer cells upon MEVs treatment.

Repurposing of Antibiotic Sulfisoxazole Inhibits Lipolysis in Pre-Clinical Model of Cancer-Associated Cachexia

“…Recently, repurposing of an FDA-approved oral antibiotic, sulfisoxazole (SFX), in pre-clinical breast cancer models demonstrated its anti-tumour and anti-metastatic effects [ 30 ]. It has been proposed that SFX treatment reduces the release of extracellular vesicles, small membranous vesicles released by cells [ 31 , 32 ], and thereby reduces metastasis of these cancer cells. However, another study failed to confirm this finding that SFX reduces the release of extracellular vesicles by cancer cells [ 33 ].…”

Extracellular Vesicles from Animal Milk: Great Potentialities and Critical Issues

“…These vesicles were able to increase the production of proangiogenic growth factors, which led to improved motility, migration, and tube formation of endothelial cells after oxygen and glucose deprivation and alleviated cardiac fibrosis in rats [ 188 ]. Bovine mEVs were also tested on the cancer cells of neuroblastoma (NBL) and melanoma; this decreased the cell proliferation and increased the susceptibility to antitumoral drugs through the depletion of proteins related to metabolism cell growth and Wnt signaling in the NBL cells [ 189 ]. A particular role of bovine mEV miR-2478 in inhibiting melanin production and melanogenesis in melanoma cells was found to be acting in the repression of the expression of Rap1, a protein that is involved in melanin synthesis and takes part in the Akt-GSK3β signal pathway [ 190 ].…”

Perspectives on Bovine Milk-Derived Extracellular Vesicles for Therapeutic Applications in Gut Health

“…Milk EVs promote osteoblastogenesis, increase the number of osteocytes, and have been shown to increase bone mineral density ( Oliveira et al., 2016 ; Oliveira et al, 2017 ; Oliveira et al, 2020 ; Yun et al, 2020 ). They exert beneficial effect on reproduction ( Sadri et al, 2020 ), cardiac fibrosis ( Zhang et al, 2021 ), arthritis ( Arntz et al, 2015 ), cancer ( Fonseka et al, 2021 ; Samuel et al, 2021 ), melanogenesis ( Bae and Kim, 2021 ), and scar-free wound healing ( Ahn et al, 2021 ). Milk EVs have been reported to exhibit biological effects in various case, but precise mechanistic studies and human trials are essential to define a strategy to leverage milk EVs as therapeutics.…”