Esculetin supresses EMT phenotype in colon carcinoma cells and induces differentiation in leukemic blast cells accompanying reduced cancer stem cell properties Esculetin supresses EMT phenotype in colon carcinoma cells and induces differentiation in leukemic blast cells accompanying reduced cancer stem cell properties Ankit Mathur, Daman Saluja Dr. B.R. Ambedkar Center for Biomedical Research, University of Delhi, Delhi, India The intra-tumoural heterogeneity partially attributed to clonal evolution of transforming tumour cells results in a complex sub-clonal hierarchical organization and therapy resistance. The phenotypic trans-differentiation of the cancer cells can be best explained by Epithelial-Mesenchymal Transition (EMT) in solid tumours as well as accumulated immature blast cells endowed with cancer stem cell (CSC) properties in Acute Myeloid Leukemia (AML). We have previously demonstrated anti-proliferative, anti-leukemic, and anti-oxidative effects of natural compound (Esculetin) on AML and pancreatic cancer cells. The current study supports the rationale of using esculetin to force transdifferentiating cells to undergo a less aggressive counterpart. The Trans-differentiating potential of esculetin was assessed on two in vitro cellular models using AML cells (Kasumi-1cell line) with t(8;21/AML-ETO) translocation as well as human colon carcinoma cell line (HCT116) with p53 and p73 knockdowns. Three HCT116 cell strains with sequential knockdown of p53 and p73 genes progressively exhibited altered morphology indicative of acquisition of mesenchymal property. EMT marker expressions and Wnt activation coupled with anchorage independent growth, anoikis resistance, enhanced cell mobility, and saturation density confirmed progressive transformation accompanying EMT. Esculetin (100μM), exerted cytostatic effect with reduced aggressiveness and reversion of EMT phenotypes in HCT116 strains. Interestingly, morphological alterations associated with neutrophilic differentiation as well as corresponding acquisition of myeloid lineage markers indicate terminal differentiation potential of esculetin in leukemic blasts. The study highlights the possibility that the cells that escaped the early apoptosis program were stimulated to undergo differentiation upon esculetin treatment. Esculetin also showed potential to revert the CSC marker expressions consistent with reduced functional CSC properties and suppression of Wnt associated genes in colon cancer as well as leukemic cells. Thus, the study may provide significant therapeutic innervations of esculetin as a differentiating agent in both solid cancers as well as in leukemia.
Dr. B.R. Ambedkar Center for Biomedical Research, University of Delhi
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