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.
|Number of pages||16|
|Journal||Journal of Biological Chemistry|
|State||Published - May 31 2019|
Bibliographical noteFunding Information:
This work was supported in part by NCI, National Institutes of Health, Grant R01CA222596; Department of Defense Grant W81XWH-16-1-0203; Ameri-can Cancer Society Grant RSG-16-213-01-TBE; and Kentucky Lung Cancer Research Program Grant KLCRP2016. The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or other funding agencies.
© 2019 Chawsheen et al.
ASJC Scopus subject areas
- Molecular Biology
- Cell Biology