APR-246/PRIMA-1(MET) inhibits thioredoxin reductase 1 and converts the enzyme to a dedicated NADPH oxidase

作者：Peng X; Zhang M Q Z; Conserva F; Hosny G; Selivanova G; Bykov V J N; Arner E S J^*; Wiman K G

来源：Cell Death & Disease, 2013, 4(10): e881.

DOI：10.1038/cddis.2013.417

• APR-246
• PRIMA-1(MET)
• thioredoxin reductase 1
• mutant p53
• ROS

The low-molecular-weight compound APR-246 (PRIMA-1(MET)) restores wild-type conformation and function to mutant p53, and triggers apoptosis in tumor cells. We show here that APR-246 also targets the selenoprotein thioredoxin reductase 1 (TrxR1), a key regulator of cellular redox balance. APR-246 inhibited both recombinant TrxR1 in vitro and TrxR1 in cells. A Sec-to-Cys mutant of TrxR1 was not inhibited by APR-246, suggesting targeting of the selenocysteine residue in wild-type TrxR1. Preheated APR-246 and its conversion product methylene quinuclidinone (MQ) were much more efficient TrxR1 inhibitors than APR-246 itself, indicating that MQ is the active compound responsible for TrxR1 enzyme inhibition. TrxR1 inhibited by MQ was still functional as a pro-oxidant NADPH oxidase. Knockdown of TrxR1 caused a partial and reproducible attenuation of APR-246-induced tumor cell death independently of p53 status. Cellular TrxR1 activity was also inhibited by APR-246 irrespective of p53 status. We show that APR-246 can directly affect cellular redox status via targeting of TrxR1. Our findings provide an explanation for the previously observed effects of APR-246 on tumor cells lacking mutant p53.

• 出版日期2013-10