Morusin reverses paclitaxel resistance by inhibiting the stem cell-like properties of non-small cell lung cancer in a β-catenin-dependent manner

Drug resistance is the common factor inducing failure of chemotherapy for non-small cell lung Cancer (NSCLC), whereas β-catenin-regulated stem cell-like characteristics exert an important effect on tumor cell resistance. Antitumor activity of morusin is well established; however, its impact on paclitaxel (PTX) resistance of NSCLC is largely unexplored. The present work successfully established PTX-resistant NSCLC cells, and applied morusin as an intervention. We used methylthiazolyldiphenyl-tetrazolium bromide assay for assessing drug resistance level. Apoptosis rate was measured through flow cytometry. Additionally, stem cell characteristics marker expression (ALDH1, SOX2, OCT4, and NANOG) was analyzed through quantitative real-time polymerase chain reaction. We also conducted tumor sphere formation assay for evaluating stem cell-like properties in NSCLC cells. Immunofluorescence and Western blotting assays were performed to examine β-catenin protein level and localization. Ultimately, we established PTX-resistant NSCLC cell lines with β-catenin overexpression to investigate the potential molecular mechanisms underlying morusin's ability to reverse PTX resistance of NSCLC cells. As suggested by our findings, PTX-resistant NSCLC cells exhibited reduced PTX susceptibility, augmented stem cell-like properties, upregulated β-catenin, and enhanced β-catenin nuclear accumulation. Morusin effectively reversed PTX resistance, enhanced PTX-induced Apoptosis, and attenuated stem cell-like properties of PTX-resistant NSCLC cells. Interestingly, morusin downregulated β-catenin protein level while inhibiting the nuclear translocation of PTX-resistant NSCLC cells. However, β-catenin overexpression significantly augmented both resistance to PTX and stem cell-like properties in PTX-resistant NSCLC cells. Moreover, effects induced by morusin on these phenomena were effectively counteracted by the overexpression of β-catenin. In conclusion, morusin may reverse resistance of NSCLC cells to PTX through suppressing β-catenin-mediated stem cell-like properties. SIGNIFICANCE STATEMENT: Cancer Stem Cells represent the most fundamental cause of drug resistance. Morusin can enhance the efficacy of paclitaxel by inhibiting β-catenin-mediated stem cell-like properties in non-small cell lung Cancer cells, and thus holds promise for contributing to the clinical management of paclitaxel resistance.

Morusin; Non–small cell lung cancer; Paclitaxel; Stem cell–like property; β-Catenin.