HIF-1 and NRF2; Key Molecules for Malignant Phenotypes of Pancreatic Cancer

SIMPLE SUMMARY: Pancreatic cancer progression involves interactions between cancer cells and stromal cells in harsh tumor microenvironments, which are characterized by hypoxia, few nutrients, and oxidative stress. Clinically, cancer cells overcome therapeutic interventions, such as chemotherapy and radiotherapy, to continue to survive. Activation of the adaptation mechanism is required for cancer cell survival under these conditions, and it also contributes to the acquisition of the malignant phenotype. Stromal cells, especially pancreatic stellate cells, play a critical role in the formation of a cancer-promoting microenvironment. We here review the roles of key molecules, hypoxia inducible factor-1 and KEAP1-NRF2, in stress response mechanisms for the adaptation to hypoxia and oxidative stress in pancreatic cancer cells and stellate cells. Various cancer-promoting properties associated with these molecules have been identified, and they might serve as novel therapeutic targets in the future. ABSTRACT: Pancreatic cancer is intractable due to early progression and resistance to conventional therapy. Dense fibrotic stroma, known as desmoplasia, is a characteristic feature of pancreatic cancer, and develops through the interactions between pancreatic cancer cells and stromal cells, including pancreatic stellate cells. Dense stroma forms harsh tumor microenvironments characterized by hypoxia, few nutrients, and oxidative stress. Pancreatic cancer cells as well as pancreatic stellate cells survive in the harsh microenvironments through the altered expression of signaling molecules, transporters, and metabolic enzymes governed by various stress response mechanisms. Hypoxia inducible factor-1 and KEAP1-NRF2, stress response mechanisms for hypoxia and oxidative stress, respectively, contribute to the aggressive behaviors of pancreatic cancer. These key molecules for stress response mechanisms are activated, both in pancreatic cancer cells and in pancreatic stellate cells. Both factors are involved in the mutual activation of cancer cells and stellate cells, by inducing cancer-promoting signals and their mediators. Therapeutic interventions targeting these pathways are promising approaches for novel therapies. In this review, we summarize the roles of stress response mechanisms, focusing on hypoxia inducible factor-1 and KEAP1-NRF2, in pancreatic cancer. In addition, we discuss the potential of targeting these molecules for the treatment of pancreatic cancer.