title: Ape1 regulates WNT/β-catenin signaling through its redox functional domain in pancreatic cancer cells.
abstract: Apurinic/apyrimidinic endonuclease 1/redox factor-1 (Ape1/Ref-1, Ape1) is a multifunctional protein that is upregulated in human pancreatic cancer. Ape1 redox domain plays an essential role in regulating the effects of reactive oxygen species (ROS) generated during physiological metabolism and pathological stress. In the present study, we explored whether Ape1 and ROS affect WNT/β-catenin signaling. We used E3330, a small molecule inhibitor of the redox activity of Ape1, and a siRNA approach to knock down Ape1, in two human pancreatic cancer cell lines. Inhibition of Ape1 resulted in growth suppression of pancreatic cancer cells, increased ROS levels, upregulation of β-catenin and c-myc and downregulation of cyclin D1. Consistent with these data, overexpression of Ape1 in pancreatic cancer cells reduced ROS and c-myc levels and increased cyclin D1 levels. Moreover, treatment of pancreatic cancer cells with H2O2 to induce oxidative stress resulted in upregulated ROS levels, decreased Ape1 at both the mRNA and protein level, and alterations in WNT/β-catenin pathway components. Finally, treatment of pancreatic cancer cells with the WNT/β-catenin inhibitor IWR-1 resulted in growth inhibition, which was greatly enhanced when combined with E3330 treatment. In summary, our results demonstrate that ROS is an important intracellular messenger that can modulate WNT/β‑catenin signaling. The present study provides interesting new insight into crosstalk between the redox function of Ape1 and WNT/β-catenin signaling in cancer cells. Furthermore, our data show that the combination of Ape1 and WNT inhibitors enhanced the inhibition of pancreatic cell proliferation. These results provide a promising novel therapeutic strategy for treating pancreatic cancer in future.
authors.affiliation: Department of Radiology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310016, P.R. China.
authors.forename: Shaojie
authors.initials: S
authors.lastname: Jiang
authors.affiliation: Department of Ophthalmology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, P.R. China.
authors.forename: Lina
authors.initials: L
authors.lastname: Zhu
authors.affiliation: Biomedical Research Center, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310016, P.R. China.
authors.forename: Haimei
authors.initials: H
authors.lastname: Tang
authors.affiliation: Department of Orthopaedics, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310009, P.R. China.
authors.forename: Miaofeng
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Xin Hua Hospital, Shanghai Key Laboratory for Pediatrics Gastroenterology and Nutrition, Shanghai Institute for Pediatrics Research, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, P.R. China.
authors.forename: Zhihua
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Department of Surgery, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200025, P.R. China.
authors.forename: Jian
authors.initials: J
authors.lastname: Fei
authors.affiliation: Department of Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, P.R. China.
authors.forename: Baosan
authors.initials: B
authors.lastname: Han
authors.affiliation: Xin Hua Hospital, Shanghai Key Laboratory for Pediatrics Gastroenterology and Nutrition, Shanghai Institute for Pediatrics Research, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, P.R. China.
authors.forename: Gang-Ming
authors.initials: GM
authors.lastname: Zou
mesh_terms: D016227:Benzoquinones / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007094:Imides / Q000494:pharmacology; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D011422:Propionates / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D060449:Wnt Signaling Pathway / Q000187:drug effects
chemical_list: D016227:Benzoquinones; C585534:IWR-1 compound; D007094:Imides; D011422:Propionates; D011804:Quinolines; D017382:Reactive Oxygen Species; C075569:E 3330; D006861:Hydrogen Peroxide; C085108:APEX1 protein, human; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase