Lusianthridin Targeting of Lung Cancer Stem Cells via Src-STAT3 Suppression

Background Cancer stem cells (CSCs) are well-recognized as a majority cause of treatment failure and can give rise to relapse. The discovery of compounds attenuating CSCs’ properties is crucial for enabling advances in novel therapeutics to limit recurrence. CSCs’ features in lung cancer are regulated through a reduction in Src-STAT3-c-Myc, which drives cancer progression, drug resistance, and metastasis. Methods The effect of lusianthridin suppresses CSC-like phenotypes was determined by 3D culture and anchorage independent growth. The expression of CSC markers and associated proteins were determined by Western blot analyses. Protein ubiquitination and degradation were assessed using immunoprecipitation. Results Herein, we report that lusianthridin, a pure compound from Dendrobium venustum , dramatically suppressed CSCs in lung cancer cells as verified by several CSC phenotype assessments and CSC markers. The CSC phenotypes in lusianthridin-treated cells were suppressed through downregulation of Src-STAT3-c-Myc pathways. Ectopic Src introduced by the transfection augmented CSC phenotypes in lung cancer cells through STAT3 (increased active p-STAT3 Tyr705 ) and c-Myc signals, while the ShRNA-Src transfection or Src inhibitor dasatinib exhibited opposite results. Treatment of the Src-overexpressing cells with lusianthridin resulted in the reversal of active STAT3 (p-STAT3 Tyr705 ) and c-Myc as well as the CSC marker CD133. Importantly, we confirmed the CSC-targeted activity of lusianthridin in CSC-rich primary lung cancer cells. The compound dramatically inhibited the formation of tumor spheres of primary lung cancer cells. Finally, we demonstrated that after CSC-attenuation by lusianthridin, the lung cancer cells exhibited significantly higher susceptibility to chemotherapeutic drugs. Such a sensitizing effect caused by pro-survival suppression and pro-apoptotic induction together with the abolishment of stemness indicated by the decrease in CSC markers CD133, ABCG2, and ALDH1A1. Conclusion These findings revealed a novel pharmacological action and the underlying mechanism of lusianthridin in negatively regulating CSC-like phenotypes and sensitizing resistant cancer cells to cemetery.