The Role of APE1 in Mitochondrial Metabolism

Pancreatic ductal adenocarcinoma (PDAC) is the 4th leading cause of cancer related mortality in the United States, and is accompanied by a fibrotic phenotype that contributes to chemotherapeutic  resistance. Combination therapies including Gemcitabine (GemzarTM) and sustained release, nab-paclitaxel (AbraxaneTM) and FOLFIRINOX (5-FU/leucovorin/irinotecan/oxaliplatin) offer modest improvement in survival, albeit at an increase in side effects.

A novel PDAC target, Apurinic/apyrimidinic endonuclease/redox factor-1 (APE1/Ref-1 or APE1) is a multifunctional proteininvolved in repairing DNA damage via endonuclease activity and in redox regulation of transcription factors like HIF-1α, STAT3,NFκB and others. APE1 is essential for cell viability, whichprevents generation of a stable APE1-knockout cell line. APE1 siRNA knockdowns are also transient, which means techniques like bulk RNA-seq are unable to generate a comprehensive list of
genes regulated by APE1.

In this study we analyze the role of APE1 in mitochondrial metabolism. We also show how the combination of targeting APE1 redox function along with mitochondrial metabolism enhances tumor efficacy.