Abstract
BackgroundThe expansion and metastasis of colorectal cancers are closely associated with the dynamic growth of cancer stem cells (CSCs). This study aimed to explore the possible effect of LXR (a regulator of glycolysis and lipid hemostasis) in the tumorgenicity of human colorectal CD133 cells.MethodsHuman HT-29 CD133+ cells were enriched by MACS and incubated with LXR agonist (T0901317) and antagonist (SR9243) for 72 h. Cell survival was evaluated using MTT assay and flow cytometric analysis of Annexin-V. The proliferation rate was measured by monitoring Ki-67 positive cells using IF imaging. The modulation of LXR was studied by monitoring the activity of all factors related to ABC transporters using real-time PCR assay and western blotting. Protein levels of metabolic enzymes such as PFKFB3, GSK3β, FASN, and SCD were also investigated upon treatment of CSCs with LXR modulators. The migration of CSCs was monitored after being exposed to LXR agonist using scratch and Transwell insert assays. The efflux capacity was measured using hypo-osmotic conditions. The intracellular content of reactive oxygen species was studied by DCFH-DA staining.ResultsData showed incubation of CSCs with T0901317 and SR9243 reduced the viability of CD133 cells in a dose-dependent manner compared to the control group. The activation of LXR up-regulated the expression and protein levels of ABC transporters (ABCA1, ABCG5, and ABCG8) compared to the non-treated cells (p < 0.05). Despite these effects, LXR activation suppressed the proliferation, clonogenicity, and migration of CD133 cells, and increased hypo-osmotic fragility (p < 0.05). We also showed that SR9243 inhibited the proliferation and clonogenicity of CD133 cells through down-regulating metabolic enzymes PFKFB3, GSK3β, FASN, and SCD as compared with the control cells (p < 0.05). Intracellular ROS levels were increased after the inhibition of LXR by SR9243 (p < 0.05).Calling attention, both T0901317 and SR9243 compounds induced apoptotic changes in cancer stem cells (p < 0.05).ConclusionsThe regulation of LXR activity can be considered as a selective targeting of survival, metabolism, and migration in CSCs to control the tumorigenesis and metastasis in patients with advanced colorectal cancers.
Highlights
The expansion and metastasis of colorectal cancers are closely associated with the dynamic growth of cancer stem cells (CSCs)
The regulation of Liver X receptors (LXRs) activity can be considered as a selective targeting of survival, metabolism, and migration in CSCs to control the tumorigenesis and metastasis in patients with advanced colorectal cancers
Student t-test and One-Way ANOVA with Tukey posthoc analysis. *p < 0.05, **p < 0.01, and ***p < 0.001 we found that the activation of LXR is closely related to the function of ATP-binding cassette transport‐ ers (ABCs) transporters in which the mean CSC diameter increased in early 15 minutes incubated in hypo-osmotic conditions
Summary
The expansion and metastasis of colorectal cancers are closely associated with the dynamic growth of cancer stem cells (CSCs). This study aimed to explore the possible effect of LXR (a regulator of glycolysis and lipid hemostasis) in the tumorgenicity of human colorectal CD133 cells. The migration of CSCs was monitored after being exposed to LXR agonist using scratch and Transwell insert assays. Dianat‐Moghadam et al Cancer Cell Int (2021) 21:100 population of CSCs which causes drug resistance, tumorigenesis, recurrence, and metastasis [3]. These cells could need on-demand energy for bioactivity and differentiation during the cancer stroma [4]. The CHOL content acts as putative mitogen through SREBP-2 (sterol regulatory element-binding protein) expression that promotes the proliferation and tumorigenesis of intestinal stem cells [6]. It has shown that the lipid raft membrane-localized matrix metalloproteinase-2 induces the migration of stem cells through degrading the ECM and activation of matrix metalloproteinase-9 [7]
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