ROLE OF MITOCHONDRIA IN RESPONSE TO ATO/D-VC TREATMENT IN KRAS MUTANT CANCER CELLS

Abstract

Kirsten rat sarcoma (KRAS) is a prevalent oncogene which is associated with pancreatic, colorectal and lung cancers. KRAS is frequently mutated in variety of tumors and is linked to poor prognosis around the world. According to growing body of literature, one of main features of KRAS mutated cancer cells is a dysregulated glucose metabolism and continuously activated signaling pathways. Therefore, it became an attractive target to investigate cancer proliferation and adaptation response to various treatment strategies. One of such targeted therapies is recently proposed combination of arsenic trioxide (ATO) and D isoform of Vitamin C (D-VC). It inflicts potent synergistic effect on cancer cells by inducing significant cytotoxic stress ultimately leading to cell death. It was found that this novel ATO and D-VC combined treatment induces apoptosis in the mouse KRAS pancreatic adenocarcinoma cells by stimulating the suicidal mitochondrial reactive oxygen species (ROS) production. One potential target site of this treatment are mitochondria. It is unknown, whether similar response can be achieved in KRAS mutant cancer cells depleted of mitochondria. In this study, we aimed to investigate the role of mitochondria in cells as a pivotal player in response to ATO/D-VC treatment.