Abstract
BackgroundAdaptive drug resistance is an unfavourable prognostic factor in cancer therapy. Pemetrexed-resistant lung cancer cells possess high-metastatic ability via ERK–ZEB1 pathway-activated epithelial–mesenchymal transition. GMI is a fungal immunomodulatory protein that suppresses the survival of several cancer cells.MethodsCell viability was analysed by MTT, clonogenic, tumour spheroid, and cancer stem cell sphere assays. Western blot assay was performed to detect the protein expression. Chemical inhibitors and ATG5 shRNA were used to inhibit autophagy. Tumour growth was investigated using xenograft mouse model.ResultsGMI decreased the viability with short- and long-term effects and induced autophagy but not apoptosis in A549/A400 cells. GMI downregulated the expression levels of CD133, CD44, NANOG and OCT4. GMI induces the protein degradation of CD133 via autophagy. CD133 silencing decreased the survival and proliferation of A549/A400 cells. GMI suppressed the growth and CD133 expression of A549/A400 xenograft tumour.ConclusionsThis study is the first to reveal the novel function of GMI in eliciting cytotoxic effect and inhibiting CD133 expression in pemetrexed-resistant lung cancer cells via autophagy. Our finding provides evidence that CD133 is a potential target for cancer therapy.
Highlights
Adaptive drug resistance is an unfavourable prognostic factor in cancer therapy
Cell shrinkage and lower density were induced by GMI in A549/ A400 cells (Fig. 1a)
MTT assay showed that GMI inhibited the viability of A549/A400 cells in a dose- and time-dependent manner (Fig. 1b)
Summary
Adaptive drug resistance is an unfavourable prognostic factor in cancer therapy. Pemetrexed-resistant lung cancer cells possess high-metastatic ability via ERK–ZEB1 pathway-activated epithelial–mesenchymal transition. GMI is a fungal immunomodulatory protein that suppresses the survival of several cancer cells. RESULTS: GMI decreased the viability with short- and long-term effects and induced autophagy but not apoptosis in A549/A400 cells. GMI induces the protein degradation of CD133 via autophagy. GMI suppressed the growth and CD133 expression of A549/A400 xenograft tumour. CONCLUSIONS: This study is the first to reveal the novel function of GMI in eliciting cytotoxic effect and inhibiting CD133 expression in pemetrexed-resistant lung cancer cells via autophagy. Autophagosomes dock lysosomes and fuse as autolysosomes to degrade the engulfed cargos by lysosomal enzymes.[3] An appropriate level of autophagy protects cells from stress, but a high level of autophagy triggers autophagic cell death.[4] Autophagy-mediated cell death is a new strategy for anti-cancer drug development
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