Small-molecule inhibitor of the AP endonuclease 1/REF-1 E3330 inhibits pancreatic cancer cell growth and migration.
AP endonuclease 1 (APE1; also known as REF-1) contains a DNA repair domain and a redox regulation domain. APE1 is overexpressed in several human cancers, and disruption of APE1 function has detrimental effects on cancer cell viability. However, the selective contribution of the redox and the DNA repair domains to maintenance of cellular homeostasis in cancer has not been elucidated. In the present study, we used E3330, a small-molecule inhibitor of APE1 redox domain function, to interrogate the functional relevance of sustained redox function in pancreatic cancer. We show that E3330 significantly reduces the growth of human pancreatic cancer cells in vitro. This phenomenon was further confirmed by a small interfering RNA experiment to knockdown APE1 expression in pancreatic cancer cells. Further, the growth-inhibitory effects of E3330 are accentuated by hypoxia, and this is accompanied by striking inhibition in the DNA-binding ability of hypoxia-inducible factor-1alpha, a hypoxia-induced transcription factor. E3330 exposure promotes endogenous reactive oxygen species formation in pancreatic cancer cells, and the resulting oxidative stress is associated with higher levels of oxidized, and hence inactive, SHP-2, an essential protein tyrosine phosphatase that promotes cancer cell proliferation in its active state. Finally, E3330 treatment inhibits pancreatic cancer cell migration as assessed by in vitro chemokine assays. E3330 shows anticancer properties at multiple functional levels in pancreatic cancer, such as inhibition of cancer cell growth and migration. Inhibition of the APE1 redox function through pharmacologic means has the potential to become a promising therapeutic strategy in this disease.
Zou
Gang-Ming
GM
Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, 1550 Orleans Street, CRB-2, M341, Baltimore, MD 21231, USA. gzou1@jhmi.edu
Maitra
Anirban
A
D016227:Benzoquinones / Q000494:pharmacology*; D015687:Cell Hypoxia / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D054377:Chemokine CXCL12 / Q000378:metabolism; D004273:DNA, Neoplasm / Q000378:metabolism; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000037:antagonists & inhibitors*; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004847:Epithelial Cells / Q000187:drug effects / Q000473:pathology; D016193:G1 Phase / Q000187:drug effects; D016195:G2 Phase / Q000187:drug effects; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D008954:Models, Biological; D010084:Oxidation-Reduction / Q000187:drug effects; D010179:Pancreas / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000201:enzymology* / Q000473:pathology*; D011422:Propionates / Q000494:pharmacology*; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism
D016227:Benzoquinones; D054377:Chemokine CXCL12; D004273:DNA, Neoplasm; D004791:Enzyme Inhibitors; C497442:HIF1A protein, human; D018960:Hyaluronan Receptors; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D011422:Propionates; D017382:Reactive Oxygen Species; C075569:E 3330; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; C085108:APEX1 protein, human; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase