Sulfiredoxin Promotes Colorectal Cancer Cell Invasion and Metastasis through a Novel Mechanism of Enhancing EGFR Signaling

Abstract

Sulfiredoxin (SRXN1/Srx) is a multifunction enzyme with a primary antioxidant role of reducing the overoxidized inactive form of peroxiredoxins (Prxs). The function and mechanisms of Srx in cancer development are not well understood. Here, Srx is preferentially expressed in human colorectal cancer (CRC) cells but not in normal colon epithelial cells. Loss-of-function studies demonstrate that knockdown of Srx in poorly differentiated CRC cells not only leads to the inhibition of colony formation and cell invasion in vitro, but also reduces tumor xenograft growth and represses metastasis to distal organs in a mouse orthotopic implantation model. Notably, exactly opposite effects were observed in gain-of-function experiments when Srx was ectopically expressed in well-differentiated CRC cells. Mechanistically, expression of Srx enhances the activation of mitogen activated protein kinase (MAPK) signaling through increasing the C-terminal tyrosine phosphorylation levels of epidermal growth factor receptor (EGFR). This function of Srx is mediated through its inhibition of EGFR acetylation at K1037, a novel post-translational modification of EGFR in human CRC cells identified by liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS) proteomic analysis. Furthermore, abolishment of K1037 acetylation in human CRC cells by site-specific mutagenesis leads to sustained activation of EGFR-MAPK signaling. Combined, these data reveal that Srx promotes CRC cell invasion and metastasis through a novel mechanism of enhancing EGFR signaling. Implications Sulfiredoxin is a critical oncogenic protein that can be used as a molecular target to develop therapeutics for patients with metastatic colorectal cancer.

Activation of Epidermal Growth Factor Receptor/p38/Hypoxia-inducible Factor-1α Is Pivotal for Angiogenesis and Tumorigenesis of Malignantly Transformed Cells Induced by Hexavalent Chromium

“…shRNAs of EGFR, MMP-1, and HIF-1␣ were from Origene (Rockville, MD). p3XFLAG-CMV/EGFR and its control plasmids were kindly provided by Dr. Qiou Wei (Department of Toxicology and Cancer Biology, University of Kentucky) (58). Bradford protein assay reagent was from Bio-Rad.…”

Association between loss of Y chromosome and poor prognosis in male head and neck squamous cell carcinoma

“…Disruption of redox homeostasis, resulting in elevated levels of reactive oxygen species in tumor cells has been implicated in the promotion of tumor progression and development of drug resistance . Genes upregulated in LoY compared with non‐LoY cases included members of the AKRs superfamily of NAD(P)H‐linked oxidoreductases, such as AKR1B10, AKR1C1, AKR1C2, AKR1C3, as well as ALDH3A1, G6PD, GPX2, PIR, SRXN1, and TXNRD1, which are increasingly recognized for their important roles in drug detoxification and xenobiotic metabolism . In particular, the upregulation of AKR1C1, AKR1C2, and G6PD are all associated with resistance to cisplatin‐based chemotherapy in lung cancer, whereas upregulation of AKR1C3 is linked to insensitivity to radiotherapy in oesophageal cancer .…”

“…34 Genes upregulated in LoY compared with non-LoY cases included members of the AKRs superfamily of NAD(P)H-linked oxidoreductases, such as AKR1B10, AKR1C1, AKR1C2, AKR1C3, as well as ALDH3A1, G6PD, GPX2, PIR, SRXN1, and TXNRD1, which are increasingly recognized for their important roles in drug detoxification and xenobiotic metabolism. [24][25][26][35][36][37][38][39][40][41][42] In particular, the upregulation of AKR1C1, AKR1C2, and G6PD are all associated with resistance to cisplatin-based chemotherapy in lung cancer, 24,26 whereas upregulation of AKR1C3 is linked to insensitivity to radiotherapy in oesophageal cancer. 25 In a recent study of head and neck cancer, tumor redox was associated with poorer patient outcomes, suggesting that its measurement, for example, by 62Cu-ATSM PET, could be a useful prognostic marker.…”

Mutant EGFR is a preferred SMURF2 substrate of ubiquitination: role in enhanced receptor stability and TKI sensitivity

“…Earlier studies have indicated that K721 and K846 residues of EGFR are important for maintaining EGFR kinase activity, whereas, K1037 and K1164 are important sites of acetylation required for receptor internalization (30). In another study, Jiang et al reported that inhibition of K1037 acetylation by an oncogenic protein, Sulfiredoxin (Srx), can promote sustained EGFR activation (37). Taken together, we hypothesize that SMURF2-UBCH5-mediated ubiquitination at K721 and K846 residues may be critical in constitutive activation of the mutant EGFR, whereas, ubiquitination at K1037 and 1164 may be competing with acetylation to balance receptor internalization, membrane retention, and protein stability.…”