Analysis of Kaempferol effects in suppression of epithelial-mesenchymal transition-induced chemoresistance in Oral Squamous Cell Carcinoma

Abstract

During Oral Carcinogenesis, neoplastic cells acquire an aggressive phenotype, resulting in an increase in motility, ability to invade surrounding tissues and to metastasize. The acquisition of this aggressive phenotype, which is associated with the Epithelial-Mesenchymal Transition (EMT) process, is dependent on genetic and epigenetic modifications and on the interactions of tumor cells with cellular and non-cellular components of the tumor microenvironment. Several studies suggest that EMT is directly related to the acquisition of chemoresistance of neoplastic cells and, consequently, associated with a worse prognosis in Oral Squamous Cell Carcinoma (OSCC). One of the most studied mechanisms of EMT induction is dependent on the activity of TGF-², produced by the tumor cells (autocrine pathway) or by stromal components (paracrine pathway), including Cancer-Associated Fibroblasts (CAFs). Kaempferol, a natural flavonoid found in many dietary plant sources, has multifaceted biological and pharmacological properties, including antitumor properties, and it has been pointed out that it may inhibit TGF-²1-dependent EMT, thus being associated with the reversal of cisplatin-induced chemoresistance. The aim of the present study will be to evaluate the effects and regulatory mechanisms triggered by treatment with Kaempferol on the inhibition of EMT in OSCC cell lines, with and without induction of cisplatin chemoresistance, in the presence of CAFs in a 3D spheroid culture model. Initially, the OSCC strains (SCC-9 and HSC-3), alone or in complex spheroids with CAFs, will be treated with different concentrations of Kaempferol and the possible repressor effects in EMT (in relation to its markers and phenotypes) and in cisplatin-induced chemoresistance will be evaluated. The pathways and possible targets activated by Kaempferol treatment, TGF-²-dependent and TGF-²-independent, involved in this process will be explored. It is expected with this study to characterize the effects and biological mechanisms of Kaempferol in the reversion of aggressiveness and chemoresistance to cisplatin, which are dependent on the EMT process, and to identify targets that have prognostic value for OSCC, reflecting on advances for the disease treatment. (AU)