Abstract
Simple SummaryColorectal cancer (CRC) is the second leading cause of cancer-related deaths and the most frequently diagnosed cancer type. CRC risk can be preventable by modifiable risk factors, including diet. This study provides evidence on the antiproliferative and pro-apoptotic effects of whey from Mediterranean water buffalo (Bubalus bubalis) milk in HT-29, HCT 116, LoVo, and SW480 cells. Results showed that whey induced metabolic dysfunctions and modulated the bioenergetic signature of CRC cells by targeting SIRT3 expression. These findings unveil the anti-neoplastic effects of whey and pave the way for the use of this by-product, rich in bioactive nutrients, in the setting of novel prevention strategies to reduce the risk of CRC.Emerging strategies to improve healthy aging include dietary interventions as a tool to promote health benefits and reduce the incidence of aging-related comorbidities. The health benefits of milk are also linked to its richness in betaines and short-chain acylcarnitines, which act synergistically in conferring anticancer, anti-inflammatory, and antioxidant properties. Whey, despite being a dairy by-product, still has a considerable content of bioactive betaines and acylcarnitines. Here, we investigated the anticancer properties of whey from Mediterranean water buffalo (Bubalus bubalis) milk by testing its antiproliferative effects in colorectal cancer (CRC) cells HT-29, HCT 116, LoVo and SW480. Results indicated that treatment with whey for 72 h inhibited cell proliferation (p < 0.001), induced cell cycle arrest, and apoptosis via caspase-3 activation, and modulated cell metabolism by limiting glucose uptake and interfering with mitochondrial energy metabolism with the highest effects observed in HT-29 and HCT 116 cells. At molecular level, these effects were accompanied by upregulation of sirtuin 3 (SIRT3) (p < 0.01) and peroxisome proliferator-activated receptor (PPAR)-γ expression (p < 0.001), and downregulation of lactate dehydrogenase A (LDHA) (p < 0.01), sterol regulatory-element binding protein 1 (SREBP1) (p < 0.05), and PPAR-α (p < 0.01). Transient SIRT3 gene silencing blocked the effects of whey on the LDHA, PPAR-γ, and PPAR-α protein expressions (p < 0.01) suggesting that the whey capacity of perturbating the metabolic homeostasis in CRC cell lines is mediated by SIRT3.
Highlights
In the nutritional field, the search of nutrients and bioactive food components capable of modifying the epigenetic phenomena affecting the hallmarks of aging has emerged as an attractive tool in the setting of dietary interventions to promote health benefits and decrease the incidence of aging-related comorbidities
The effect of whey on cell proliferation was assessed on non-malignant cells
The treatment for 72 h only minimally affected the viability of the normal cells, as 81.3% ± 0.70 proliferation was observable at the highest volume of whey tested (40% v/v) (Figure 1A,B)
Summary
The search of nutrients and bioactive food components capable of modifying the epigenetic phenomena affecting the hallmarks of aging has emerged as an attractive tool in the setting of dietary interventions to promote health benefits and decrease the incidence of aging-related comorbidities. One component of epigenetic regulation involves histone deacetylases, which include the histone deacetylases (class I, II, and IV) and sirtuin deacetylases (class III). The SIRT family includes seven members (SIRT1-7) of nicotine adenine dinucleotide (NAD+)-dependent enzymes involved in the regulation of cell metabolism, oxidative stress, cell survival, DNA repair, and the nutrient-sensing pathways potentially affecting health span [1,2]. The antioxidant, anti-inflammatory and anticancer properties of δ-valerobetaine, acting in synergism with other betaines, occur in endothelial cells, colorectal cancer (CRC) cells and human oral squamous cell carcinoma cells through the modulation of sirtuins [6,7,8,9]. CRC is the third most common cancer throughout the world in terms of incidence, but second in terms of mortality, with
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