(−)-Epigallocatechin gallate inhibits stemness and tumourigenicity stimulated by AXL receptor tyrosine kinase in human lung cancer cells

Abstract

Cancer stem cells (H1299-sdCSCs) were obtained from tumour spheres of H1299 human lung cancer cells. We studied low stiffness, a unique biophysical property of cancer cells, in H1299-sdCSCs and parental H1299. Atomic force microscopy revealed an average Young's modulus value of 1.52 kPa for H1299-sdCSCs, which showed low stiffness compared with that of H1299 cells, with a Young's modulus value of 2.24 kPa. (−)-Epigallocatechin gallate (EGCG) reversed the average Young's modulus value of H1299-sdCSCs to that of H1299 cells. EGCG treatment inhibited tumour sphere formation and ALDH1A1 and SNAI2 (Slug) expression. AXL receptor tyrosine kinase is highly expressed in H1299-sdcScs and AXL knockdown with siAXLs significantly reduced tumour sphere formation and ALDH1A1 and SNAI2 (Slug) expression. An AXL-high population of H1299-sdCSCs was similarly reduced by treatment with EGCG and siAXLs. Transplantation of an AXL-high clone isolated from H1299 cells into SCID/Beige mice induced faster development of bigger tumour than bulk H1299 cells, whereas transplantation of the AXL-low clone yielded no tumours. Oral administration of EGCG and green tea extract (GTE) inhibited tumour growth in mice and reduced p-AXL, ALDH1A1, and SLUG in tumours. Thus, EGCG inhibits the stemness and tumourigenicity of human lung cancer cells by inhibiting AXL. Green tea and (−)-epigallocatechin gallate (EGCG), the main constituent of green tea catechins, prevent cancer in humans, as demonstrated in phase II clinical trials, which showed that EGCG prevented colorectal adenoma recurrence and prostate cancer development from high-grade prostate intraepithelial neoplasia 1-4. Numerous investigators have reported therapeutic effects in various human cancer cell lines by combining EGCG and other green tea catechins with anticancer compounds, including anticancer drugs, nonsteroidal anti-inflammatory drugs, and phytochemicals 5,6. Because EGCG inhibits the expression of stemness marker genes and epithelialmesenchymal transition (EMT)-related genes in human cancer stem cells (CSCs) of the breast, lung, prostate and liver, CSCs are targets of EGCG for cancer prevention and therapy 7. Using atomic force microscopy (AFM), Gimzewski's laboratory first reported that metastatic cancer cells obtained from the pleural fluids of various cancer patients showed lower average Young's modulus values, indicating lower cell stiffness, than those of normal mesothelial cells from pleural effusion 8. Furthermore, they showed that treatment with green tea extract (GTE) increased the average Young's modulus values for metastatic cancer cells (i.e., reversed the values to those of normal cell stiffness levels) 9. Our previous study revealed that EGCG increased the stiffness of H1299 and Lu99 human non-small cell lung cancer (NSCLC) cells, inhibited the high expression of EMT-related proteins, such as vimentin and SLUG, and reduced cell motility 10. To investigate the inhibitory effects of EGCG on the biophysical properties of CSCs, we enriched CSCs from the tumour spheres of

Whole-transcriptome Analysis of Fully Viable Energy Efficient Glycolytic-null Cancer Cells Established by Double Genetic Knockout of Lactate Dehydrogenase A/B or Glucose-6-Phosphate Isomerase

“…While the loss of ALDHs coincides with complete loss of glucose utilization in both KO clones, the causal effect, if any, between these two events will need further investigation. Future studies will be needed to confirm if LDHA/B inhibitors could be combined with ALDH inhibitors to evoke a more significant chemotherapeutic effect of drugs and radiation (48), and could be explored with ALDH inhibitors such as (-)epigallocatechin gallate (65,66), rocaglamide A (67), NCT-501 (67), and ellagic acid (68).…”

Nutritional combinatorial impact on the gut microbiota and plasma short-chain fatty acids levels in the prevention of mammary cancer in Her2/neu estrogen receptor-negative transgenic mice

“…Studies have shown that SFN induced G1/S arrest, led to down-regulation of SEI-1 and cyclin D2, increased levels of p21 and p27 and promoted cellular senescence in breast cancer [ 16 , 17 ]. (-)-Epigallocatechin-3-gallate (EGCG), a major polyphenol in green tea, induces epigenetic modulations such as inhibition of DNA methytransferases (DNMTs) and has numerous anticarcinogenic properties both in vitro and in vivo against several cancers including breast cancer [ 18 – 22 ]. The anti-tumor mechanisms of GTPs and EGCG involve induction of cell-cycle arrest, mitochondrial-mediated apoptosis, inhibition of IL-6 and induction of tumor necrosis factor-α expression, inhibition of enzymes that regulate the glycolytic process and repression of glucose metabolism [ 8 , 23 – 25 ].…”

Fatty Acid Synthase Inhibitor G28 Shows Anticancer Activity in EGFR Tyrosine Kinase Inhibitor Resistant Lung Adenocarcinoma Models

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