Abstract
Cancer stem cells (CSCs) are an important therapeutic target. The therapeutic agents targeting CSCs should lead to improved clinical outcomes. Here we have demonstrated the CSC-suppressing activity of pongol methyl ether (PME), a pure compound from Millettia erythrocalyx. Methods: CSC-suppressing effects were evaluated by spheroid formation assay and detection of CSC markers. The related CSC cell signals were evaluated by Western blot, immunofluorescence and molecular docking analysis. Proteins affected by PME treatment were subjected to bioinformatic analysis. Protein–protein interaction (PPI) networks were constructed by the Search Tool for Interactions of Chemicals (STITCH). The Kyoto Encyclopedia of Genes and Genomes (KEGG) mapper were used to confirm the underlying pathways. Results: PME (5–25 µM) significantly suppressed the ability of lung cancer cells to form colonies, grow in an anchorage-independent manner and generate tumour spheroids. PME at 25 µM significantly decreased the CSC markers (CD133 and ALDH1A1) and pluripotent transcription factors (Oct4 and Nanog). Akt, the key upstream signal of CSC control, was significantly decreased by the PME treatment. The molecular docking indicated that PME was bound to Akt-1 with a binding affinity of −9.2 kcal/mol greater than the Akt-1 inhibitor (reference compound; CQW). The STITCH network identified a total of 15 proteins interacted in PPI networks, and Akt-1 was identified as a central protein. The KEGG mapper indicated that the selected CSC markers were mostly involved in the ‘signalling pathways regulating pluripotency of stem cells’ pathway map and Akt, Oct4 and Nanog were the regulatory proteins in the dominant pathway. In addition, PME (10–25 µM) can suppress spheroid formation and reduce CSC-specific marker expression in patient-derived primary lung cancer cells. Conclusions: Our study revealed a novel pharmacological effect and the underlying mechanism of PME that can attenuate CSC phenotypes in lung cancer cells and may be developed for lung cancer therapy.
Highlights
Lung cancer is a major public health problem worldwide with high incidence and mortality rate [1]
We confirmed the effect of pongol methyl ether (PME) on cell proliferation by colony formation assay, and the results showed that PME at 5–25 μM can significantly decrease the size of colonies (Figure 1f,g)
cancer stem cells (CSCs) phenotypes in terms of spheroid formation and anchorage-independent growth in Having demonstrated the CSC-suppressing effects of this compound in human nonsmall cell lung cancer (NSCLC) cell line, we investigated whether PME can attenuate the CSC phenotypes in patient-derived NSCLC cells
Summary
Lung cancer is a major public health problem worldwide with high incidence and mortality rate [1]. Prominent evidence shows that cancer stem cells (CSCs) in lung cancer contribute to tumour recurrence and failure of therapy [2]. CSCs have special abilities including resisting chemotherapeutic drugs, surviving in detached conditions via the anoikis resistant mechanisms and initiating new tumour at secondary site [2]. CSCs are known to maintain their stemness through the continuous induction of pluripotency transcription factors, such as Oct, Nanog and Sox-2 [2,3,4,5]. There are several means of CSC identification including the determination of CSCrelated surface markers, the detection of pluripotent transcription factors and investigation of CSC-like phenotypes. Several CSC markers have been identified and widely utilized, such as CD133, aldehyde dehydrogenase1A1 (ALDH1A1), Oct and
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