Procaine and procainamide inhibit the Wnt canonical pathway by promoter demethylation of WIF-1 in lung cancer cells.
Secreted Wingless type (Wnt) ligands have previously been shown to be involved in tumor developmental processes and oncogenesis. Aberrant promoter methylation of Wnt inhibitory factor-1 (WIF-1) is a fundamental mechanism of epigenetic silencing in human cancers. Procaine, a local anesthetic drug, and procainamide, a drug for the treatment of cardiac arrhythmias, have been reported as inhibitors of DNA methylation, causing demethylation and reactivation of methylation-silenced genes such as RARbeta and GSTP1. The promoter demethylation of WIF-1 has not previously been reported on. We demonstrated previously that WIF-1 is silenced due to promoter hypermethylation in lung cancer cell lines. In this study, we demonstrate promoter demethylation of WIF-1; restoration of WIF-1 expression, and underexpression of cytosolic beta-catenin protein and TCF reporter activity, after procaine and procainamide treatment in H460 and A549 cell lines. Our results provide the first evidence that procaine and procainamide reactivate WIF-1 in these cancer cells and downregulate the Wnt canonical pathway. These results further suggest that procaine and procainamide may have a potential use for preventing the development of lung cancer.
Gao
Zhi
Z
Department of Cardiothoracic Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, PR China.
Xu
Zhidong
Z
Hung
Ming-Szu
MS
Lin
Yu-Ching
YC
Wang
Tianyou
T
Gong
Min
M
Zhi
Xiuyi
X
Jablons
David M
DM
You
Liang
L
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000779:Anesthetics, Local / Q000494:pharmacology; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019175:DNA Methylation; D004305:Dose-Response Relationship, Drug; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism*; D011342:Procainamide / Q000494:pharmacology*; D011343:Procaine / Q000494:pharmacology*; D011401:Promoter Regions, Genetic; D012097:Repressor Proteins / Q000235:genetics*; D051153:Wnt Proteins / Q000037:antagonists & inhibitors*
D048868:Adaptor Proteins, Signal Transducing; D000779:Anesthetics, Local; D000889:Anti-Arrhythmia Agents; D012097:Repressor Proteins; C485569:WIF1 protein, human; D051153:Wnt Proteins; D011343:Procaine; D011342:Procainamide