CD133 inhibition via autophagic degradation in pemetrexed-resistant lung cancer cells by GMI, a fungal immunomodulatory protein from Ganoderma microsporum

• Published in: British journal of cancer Vol. 123; no. 3; pp. 449 - 458
• Main Authors: Hsin, I-Lun, Chiu, Ling-Yen, Ou, Chu-Chyn, Wu, Wen-Jun, Sheu, Gwo-Tarng, Ko, Jiunn-Liang
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 04.08.2020; Nature Publishing Group
• Subjects: 631/67/1059/153; 631/67/1059/2326; 631/80/474/1624; 631/80/82/39/2346; A549 Cells; AC133 Antigen - genetics; AC133 Antigen - metabolism; Animals; Apoptosis; Autophagy; Autophagy-Related Protein 5 - antagonists & inhibitors; Biodegradation; Biomedical and Life Sciences; Biomedicine; Cancer Research; Cancer therapies; CD44 antigen; Cell Line, Tumor; Cell proliferation; Cell Proliferation - drug effects; Cell Survival - drug effects; Cell viability; Cytotoxicity; Drug Resistance; Drug Resistance, Neoplasm - drug effects; Epidemiology; Fungal Proteins - administration & dosage; Fungal Proteins - pharmacology; Ganoderma - metabolism; Gene Expression Regulation, Neoplastic - drug effects; Humans; Immunologic Factors - administration & dosage; Immunologic Factors - pharmacology; Immunomodulation; Immunomodulators; Long-term effects; Lung cancer; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; Lung Neoplasms - metabolism; Male; Mesenchyme; Metastases; Mice; Molecular Medicine; Oct-4 protein; Oncology; Pemetrexed - administration & dosage; Pemetrexed - pharmacology; Phagocytosis; Proteins; Proteolysis; Stem cells; Tumors; Xenograft Model Antitumor Assays; Xenografts
• DOI: 10.1038/s41416-020-0885-8
• ISSN: 0007-0920; 1532-1827

Background 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. Methods Cell 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. Results GMI 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. 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. Our finding provides evidence that CD133 is a potential target for cancer therapy.