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.
Highlights
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 Epigallocatechin gallate (EGCG) prevented colorectal adenoma recurrence and prostate cancer development from high-grade prostate intraepithelial neoplasia[1,2,3,4]
These findings indicated that the stiffness of the H1299 cells was reversed and that motility was inhibited to the levels of the low-motile high-stiffness H1703 non-small cell lung cancer (NSCLC) cell line, as if the cells had been treated with EGCG11
Exogenous AXL expression stimulated tumour sphere formation in H1703 cells, which express AXL at lower levels than H1299 cells (Supplementary Fig. S5). These results suggest that AXL protein stimulates ALDH1A1 and SNAI2 (Slug) expression, and increases ALDH protein and ALDH activity, suggesting that AXL is related to tumour sphere formation and stemness
Summary
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[1,2,3,4]. Our experiments showed that a human NSCLC cell line, H1299, expressed high amounts of both AXL and phosphorylated AXL (p-AXL, an active form) and revealed that treating H1299 cells with AXL-targeted siRNA increased the average Young’s modulus value. These findings indicated that the stiffness of the H1299 cells was reversed and that motility was inhibited to the levels of the low-motile high-stiffness H1703 NSCLC cell line, as if the cells had been treated with EGCG11. The results suggest that AXL contributes to the stemness of H1299-sdCSCs and is a unique target for cancer prevention with EGCG
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