Harnessing (-)-epigallocatechin-3-gallate (EGCG) with chitosan-coated liposomes to modulate the radiation effect in cancer cells through alteration in the miR-139-5p-β-catenin axis.

The development of radio-resistance during radiotherapy represents a significant obstacle in cancer treatment, often resulting in recurrence and mortality. Evidence suggests that the modulations of certain signaling pathways are primarily responsible for the emergence of radio-resistance in tumour cells, and blocking these signaling pathways during radiation therapy may reduce the likelihood of radioresistance development while enhancing radiosensitivity. In this study, chitosan-coated liposomes loaded with EGCG (CHCL EGCG) were used to increase the radiosensitivity of cancer cells. This approach facilitated the sustained release of EGCG, improved bioavailability, and enhanced efficacy relative to free EGCG, and liposome-coated EGCG in HepG2, A549, and MCF7 cell lines. The chitosan component aids in the selective binding of the nanocomposite to the cancer cells. The results also indicated that the suppression of Wnt-β-catenin-stemness-EMT-proliferation axis played a significant role in the development of radiation-sensitivity in cancer cells. RNA sequencing analysis from the GEO database of the radio-resistant MDA-MB-231 cell line and patient samples further confirmed the role of Wnt-β-catenin signaling in the development of radioresistance. Overexpression of β-catenin reversed the effect of CHCL EGCG treatment. Notably, CHCL EGCG increased H3K4me3 levels within the promoter region (intron of the Pdea2 gene) of miR-139-5p, thereby elevating its expression in cancer cells. The miR-139-5p levels were already elevated in normal cells due to higher H3K4me3 marks within the promoter region, and CHCL EGCG treatment did not increase H3K4me3 marks further. Therefore, this study perhaps potentially highlights a selective mechanism for enhancing the radiation effect in cancer cells without adversely affecting the normal cells.