Sulfiredoxin inhibitor induces preferential death of cancer cells through reactive oxygen species-mediated mitochondrial damage

Hojin Kim, Gong Rak Lee, Jiwon Kim, Jin Young Baek, You Jin Jo, Seong Eun Hong, Sung Hoon Kim, Jiae Lee, Hye In Lee, Song Kyu Park, Hwan Mook Kim, Hwa Jeong Lee, Tong Shin Chang, Sue Goo Rhee, Ju Seog Lee, Woojin Jeong

Research output: Contribution to journalArticlepeer-review

33 Scopus citations

Abstract

Recent studies have shown that many types of cancer cells have increased levels of reactive oxygen species (ROS) and enhance antioxidant capacity as an adaptation to intrinsic oxidative stress, suggesting that cancer cells are more vulnerable to oxidative insults and are more dependent on antioxidant systems compared with normal cells. Thus, disruption of redox homeostasis caused by a decline in antioxidant capacity may provide a method for the selective death of cancer cells. Here we show that ROS-mediated selective death of tumor cells can be caused by inhibiting sulfiredoxin (Srx), which reduces hyperoxidized peroxiredoxins, leading to their reactivation. Srx inhibitor increased the accumulation of sulfinic peroxiredoxins and ROS, which led to oxidative mitochondrial damage and caspase activation, resulting in the death of A549 human lung adenocarcinoma cells. Srx depletion also inhibited the growth of A549 cells like Srx inhibition, and the cytotoxic effects of Srx inhibitor were considerably reversed by Srx overexpression or antioxidants such as N-acetyl cysteine and butylated hydroxyanisol. Moreover, Srx inhibitor rendered tumorigenic ovarian cells more susceptible to ROS-mediated death compared with nontumorigenic cells and significantly suppressed the growth of A549 xenografts without acute toxicity. Our results suggest that Srx might serve as a novel therapeutic target for cancer treatment based on ROS-mediated cell death.

Original languageEnglish
Pages (from-to)264-274
Number of pages11
JournalFree Radical Biology and Medicine
Volume91
DOIs
StatePublished - 1 Feb 2016

Keywords

  • Apoptosis
  • Cancer
  • Mitochondrial damage
  • Reactiveoxygenspecies
  • Sulfiredoxin

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