Deoxypodophyllotoxin induces apoptosis in non-small cell lung cancer cells by targeting the glucocorticoid receptor

Abstract

Aims

Deoxypodophyllotoxin (DPT) has been reported to exhibit diverse pharmacological activities, including anticancer effects. This study aimed to elucidate the novel molecular mechanisms underlying the anticancer properties of DPT.

Methods

The effects of DPT on non-small cell lung cancer (NSCLC) cell proliferation and apoptosis were assessed using MTT assays, colony formation assays, flow cytometry, and western blotting. Target prediction, molecular docking simulations, and gene ontology analysis were performed to identify the molecular target of DPT and evaluate the functional relevance of DPT-associated genes in NSCLC. The role of TSC22D3 in the anticancer effects of DPT was examined by overexpressing TSC22D3.

Results

DPT inhibited NSCLC cell proliferation and colony formation while inducing apoptosis, as evidenced by increased sub-G1 DNA content, annexin V-positive cells, and cleaved PARP and caspase-3 expression. Notably, glucocorticoid receptor (GR) was identified as a potential molecular target of DPT. Eight genes commonly associated with NSCLC, DPT, and GR were found to negatively regulate the steroid hormone receptor signaling pathways. Molecular docking demonstrated that DPT binds to the GR ligand-binding domain with low binding energy. DPT suppressed dexamethasone-induced NSCLC cell proliferation and TSC22D3 expression, a GR target gene, with TSC22D3 overexpression partially rescuing cell viability. GR inhibition by mifepristone mimicked the effects of DPT. High GR expression correlated with shorter overall survival in various cancers.

Conclusions

These findings suggest that DPT exerts its anticancer effects by disrupting the GR/TSC22D3 axis in NSCLC cells, highlighting its potential as a therapeutic agent for GR-associated cancers.