Abstract
SUMMARYResearch backgroundAcquisition of migratory potential is pivotal for cancer cells, enabling invasion and metastasis of colorectal carcinoma. Royal jelly and its bioactive component trans-10-hydroxy-2-decenoic acid (10H2DA) showed remarkable antimetastatic potential, but the molecular mechanism underlying this activity is unclear.Experimental approachIdentification and quantification of 10H2DA in royal jelly originating from Serbia was done by HPLC method. Cytotoxicity of 10H2DA was measured by tetrazolium dye MTT test in concentration range 1-500 μg/mL after 24 and 72 h. Its effect on the collective and single-cell migration was measured by wound healing and transwell migration assays. Invasive potential of cancer cells was evaluated by a transwell method modified with collagen. Immunofluorescence was used for migratory and invasive protein expression, while the gene expression of these markers was evaluated by quantitative real time polymerase chain reaction (qRT-PCR). All assays were applied on human colorectal carcinoma HCT-116 and SW-480 cell lines and, except for MTT, evaluated after 24 h of treatment with two selected concentrations of royal jelly and 10H2DA.Results and conclusionsAccording to HPLC, the mass fraction of 10H2DA in royal jelly was 0.92% (m/m). Treatment with 10H2DA showed no cytotoxic effect; however, significant inhibitory potential of royal jelly and 10H2DA on the motility and invasiveness of colorectal cancer cells was observed. More pronounced effect was exerted by 10H2DA, which significantly suppressed collective cell migration and invasiveness of SW-480 cells, as well as single- and collective cell migration and invasive potential of HCT-116 cell line. Treatments increased epithelial markers E-cadherin and cytoplasmic β-catenin in HCT-116 cells, thus stabilizing intercellular connections. In SW-480 cells, 10H2DA increased E-cadherin on protein and gene level, and suppressed epithelial-mesenchymal transition (EMT) markers. In both cell lines, treatments induced significant suppression of promigratory/proinvasive markers: N-cadherin, vimentin and Snail on protein and gene level, which explains decreased migratory and invasive potential of HCT-116 and SW-480 cells.Novelty and scientific contributionOur study presents new findings and elucidation of royal jelly and 10H2DA molecular mechanism that underlies their antimigratory/antiinvasive activity on colorectal cancer cells. These findings are shown for the first time indicating that these natural products are a valuable source of anticancer potential and should be reconsidered for further antitumour therapy.
Highlights
Colorectal cancer (CRC) is the third most common type of cancer, responsible for numerous deaths worldwide [1]
Primers for E-cadherin, β-catenin and N-cadherin genes expression were from Mycrosynth (Balgach, Switzerland), while primers for Vimentin and Snail were synthesized by Metabion (Planegg, Germany)
As a result of presence of an enone system inside the lipophilic molecule of 10hydroxy-2-decenoic acid (10H2DA), the absorption maxima were batochromicaly shifted above 200 nm (Fig. 1)
Summary
Colorectal cancer (CRC) is the third most common type of cancer, responsible for numerous deaths worldwide [1]. Epithelial-mesenchymal transition (EMT) and inhibition of Wnt/β-catenin signalling pathway contribute to migratory potential of cancer cells, alongside with overexpression of promigratory/invasive proteins: N-cadherin, Snail, Vimentin, and β-catenin [4,5]. Formation of adherent junctions between neighbouring cells implies coupling of the epithelial marker E-cadherin and the intercellular protein β-catenin [6]. During metastasis, these junctions are usually dysregulated in cancer cells, whereat β-catenin becomes localized in the nuclei of cells that form an invasive front [7]. Vimentin is the marker of the mesenchymal cell phenotype and gets expressed during metastases, stimulating migration/invasiveness of CRC cells, and contributing to successful collective migration [5,6]
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