the impact of Ape/Ref1 on hypoxia regulated genes; potential applications for cancer

Pancreatic cancer is especially a deadly form of cancer with a survival rate less than 2%. Pancreatic cancers respond poorly to existing chemotherapeutic agents and radiation, and progress for the treatment of pancreatic cancer remains elusive. To address this unmet medical need, a better understanding of critical pathways and molecular mechanisms involved in pancreatic tumor development, progression, and resistance to traditional therapy is therefore critical. Reduction¿oxidation (redox) signaling systems are emerging as important targets in pancreatic cancer. AP endonuclease1/Redox effector factor 1 (APE1/Ref-1) is upregulated in human pancreatic cancer cells and modulation of its redox activity blocks the proliferation and migration of pancreatic cancer cells. Modulation of APE1/Ref-1 using the siRNA increases the HIF target, HMOX1 and NQO1,two genes that play key roles in tumor adaptation to a variety of stresses, including anticancer drugs.Ape inhibition activates the NRF2 regulator of redox stress response, which is known to regulate HMOX1 and NQO1. As all these genes are of high relevance for the acquired resistance to various antineoplastic drugs.