Kaempferol as a potential inhibitor of epithelial-mesenchymal transition and cancer stem cells in Oral Squamous Cell Carcinoma

Abstract

During oral carcinogenesis, the neoplastic cells acquire an aggressive phenotype, resulting in an increase in motility, in the ability to invade surrounding tissues and to metastasize. Metastatic spread of solid tumors is often initiated by the reactivation of an important embryonic developmental program, the Epithelial-Mesenchymal Transition (EMT). EMT has been associated with the acquisition of invasiveness and resistance to conventional therapies. During the process of tumor progression, a small fraction of cancer cells retains a self-renewal potential similar to stem cells and are referred to as Cancer Stem Cells (CSC). EMT can induce the gain of a CSC-like phenotype, therefore, effective therapies can be developed through interference of the EMT/CTC program. Kaempferol, a natural flavonoid found in several dietary plant sources, has multifaceted biological and pharmacological properties, including antitumor properties, and it has been pointed out that Kaempferol can inhibit TGF-²1-dependent EMT, thus being potentially associated with CSC phenotype inhibition in Oral Squamous Cell Carcinoma (OSCC). The aim of the present study will be to evaluate the effects and regulatory mechanisms triggered by Kaempferol treatment on inhibition of EMT/CSC in OSCC cell lines in a 3D spheroid culture model. Initially, OSCC cells (SCC-9 and HSC-3) with and without chemoresistance induction, alone or in complex spheroids with Cancer-Associated Fibroblasts (CAFs), will be treated with different concentrations of Kaempferol and the possible repressor effects on EMT/CSC (in relation to their markers and phenotypes) and cisplatin-induced chemoresistance will be evaluated. The cellular pathways and possible targets activated by Kaempferol treatment in the regulation of EMT and CSC phenotypes will also be explored. We expect to characterize the effects and biological mechanisms of Kaempferol in reversing the aggressiveness of neoplastic cells through the inhibition of the EMT/CSC program, as well as identifying targets that have prognostic value for OSCC, reflecting on advances in the treatment of cancer. (AU)