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Scutellariabarbata D. Don extraction selectively targets stemness-prone NSCLC cells by attenuating SOX2/SMO/GLI1
Wei-Wei Chen1, Kai-Kai Gong1, Li-Juan Yang1
1Center Research Institute, Binzhou Medical University Hospital, 256600, Binzhou, PR China.
Ethnopharmacological Relevance:
Scutellariabarbata D. Don extraction (SBE), a traditional Chinese medicine, has been proved effective against various malignant disorders in clinics with tolerable side-effects when administered alone or in combination with conventional chemotherapeutic regimens.
Aim Of This Study:
Multi-drug resistance of cancer is attributed to existence of cancer stemness-prone cells that harbor aberrantly high activation of Sonic Hedgehog (SHH) cascade. Our previous study has demonstrated that SBE sensitized non-small cell lung cancer (NSCLC) cells to Cisplatin (DDP) treatment by downregulating SHH pathway. Yet, whether SBE could prohibit proliferation of cancer stemness-prone cells and its underlying molecular mechanisms remain to be investigated. In this article, we further investigated intervention of SBE on NSCLC cell stemness-associated phenotypes and its potential mode of action.
Materials And Methods:
CCK-8 and clonal formation detection were used to measure the anti-proliferative potency of SBE against NSCLC and normal epithelial cells. Sphere formation assay and RQ-PCR were used to detect proliferation of cancer stemness cells and associated marker expression upon SBE incubation. Mechanistically, DARTS-WB and SPR were used to unveil binding target of SBE. Immunodeficient mice were implanted with patient derived tumor bulk for in vivo validation of anti-cancer effect of SBE.
Results:
SBE selectively attenuated proliferation and stemness-like phenotypes of NSCLC cells rather than bronchial normal epithelial cells. Drug-protein interaction analysis revealed that SBE could directly bind with stem cell-specific transcription factor sex determining region Y-box 2 (SOX2) and interfere with the SOX2/SMO/GLI1 positive loop. In vivo assay using patient-derived xenografts (PDXs) model further proved that SBE diminished tumor growth and SOX2 expression in vivo.
Conclusion:
Our data indicate that SBE represses stemness-related features of NSCLC cells via targeting SOX2 and may serve as an alternative therapeutic option for clinic treatment.
