The redox regulator sulfiredoxin forms a complex with thioredoxin domain– containing 5 protein in response to ER stress in lung cancer cells

Hedy A. Chawsheen, Hong Jiang, Qi Ying, Na Ding, Pratik Thapa, Qiou Wei

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

Abstract

Sulfiredoxin (Srx) reduces hyperoxidized 2-cysteine–containing peroxiredoxins (Prxs) and protects cells against oxidative stress. Previous studies have shown that Srx is highly expressed in primary specimens of lung cancer patients and plays a pivotal role in lung tumorigenesis and cancer progression. However, the oncogenic mechanisms of Srx in cancer are incompletely understood. In this study, we found that Srx knockdown sensitizes lung cancer cells to endoplasmic reticulum (ER) stress–induced cell death. Through MS analysis, we determined that Srx forms a complex with the ER-resident protein thioredoxin domain– containing protein 5 (TXNDC5). Using reciprocal co-immunoprecipitation, immunofluorescence imaging, subcellular fractionation, and domain-mapping assays with site-specific mutagenesis and purified recombinant proteins, we further characterized the Srx–TXNDC5 interaction. In response to ER stress but not to oxidative stress, Srx exhibits an increased association with TXNDC5, facilitating the retention of Srx in the ER. Of note, TXNDC5 knockdown in lung cancer cells inhibited cell proliferation and repressed anchorage-independent colony formation and migration, but increased cell invasion and activation of mitogen-activated protein kinases. Using immunohistochemical staining, we demonstrate that TXNDC5 is highly expressed in patient-derived lung cancer specimens. Bioinformatics analysis of publicly available data sets revealed that those with high Srx levels have significantly shorter survival and that those with high TXNDC5 levels have longer survival. We conclude that the cellular levels of Srx and TXNDC5 may be useful as biomarkers to predict the survival of individuals with lung cancer.

Original languageEnglish
Pages (from-to)8991-9006
Number of pages16
JournalJournal of Biological Chemistry
Volume294
Issue number22
DOIs
StatePublished - May 31 2019

Bibliographical note

Publisher Copyright:
© 2019 Chawsheen et al.

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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