Both colorectal cancer (CRC) and endometrial cancer (EC) remain among the most commonly diagnosed cancer types in the general population of humans [1, 2]. Depending on the cancer progression, the tumour may be surgically removed or treated with chemotherapeutics. However, chemotherapy response rates for advanced CRC and EC remain low, primarily due to intrinsic or acquired chemoresistance. Despite already described molecular mechanisms, there are other significant biochemical traits that are essential to understand in order to develop efficient therapy.
In recent years, an increasing number of studies have linked the development of malignant cells to dysregulation of signaling pathways in these cells. One such mechanism is the evolutionary conserved pathway known as Notch signaling, which is involved in the cell differentiation, proliferation and apoptosis processes. In mammals, the Notch pathway consists of four corresponding receptors (NOTCH 1-4) and five ligands (DLL1,3,4 and JAG1,2). Ligand and Notch receptor interaction activates γ-secretase protein complex, resulting in cleavage of the transmembranous Notch receptors and subsequent release of the intracellular domain (NICD). The NICD translocates into the nucleus and activates the transcription of Notch target genes by forming an activator complex with transcription factor CSL [3]. Alterations in Notch signaling pathway are proven to result in either suppressive or stimulating effect on tumor development in various cancer types, which makes it a viable therapeutic target.
To gain more insight into the significance of Notch signaling, we examined the impact of pathway suppression achieved by inhibiting γ-secretase both in colorectal cancer cells HCT116 and chemoresistant sublines HCT116/FU, HCT116/OXA as well as endometrial cancer cells KLE. We investigate the alteration of viability rate and other changes in target cell lines after applying γ-secretase inhibition alone or in combination with chemotherapeutic drugs, such as Oxaliplatin in case of colorectal cancer cells and Cisplatin and Paclitaxel in endometrial cancer cells.