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ARS Home » Pacific West Area » Davis, California » Western Human Nutrition Research Center » Diet, Microbiome and Immunity Research » Research » Publications at this Location » Publication #277589
Title: Selenoprotein W controls epidermal growth factor receptor surface expression, activation and degradation via receptor ubiquitination

Author
item Alkan, Zeynep
item Duong, Frank
item Hawkes, Wayne

Submitted to: Biochimica et Biophysica Acta
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 2/15/2015
Publication Date: N/A
Citation: N/A

Interpretive Summary: Selenium may have the potential to help prevent cancer, but some studies suggest selenium actually increases the risk of cancer. The epidermal growth factor receptor (EGFR) was the first growth factor receptor identified in cancer cells and is one of the most frequently mutated genes in human cancers. The EGFR is currently the target of intensive cancer drug development efforts. We discovered that selenoprotein W is required for epidermal growth factor to stimulate cells to grow. This helps understand how selenium affects cancer risk and may lead to development of improved cancer drugs.

Technical Abstract: Epidermal growth factor (EGF) receptor (EGFR) is the founding member of the ErbB family of growth factor receptors that modulate a complex network of intracellular signaling pathways controlling growth, proliferation and differentiation. Selenoprotein W (SEPW1) is a diet-regulated, highly conserved, ubiquitously expressed 9 kDa thioredoxin-like protein required for cell cycle progression. We report here that SEPW1 is required for EGFR signaling in human breast and prostate epithelial cells. SEPW1 depletion inhibited EGFR dimer formation and auto-phosphorylation at Tyr-992, Tyr-1045 and Tyr-1068 in response to EGF stimulation. Total EGFR was lower and EGFR half-life was shorter in SEPW1-depleted cells, suggesting an increased rate of lysosomal degradation. SEPW1 depletion reduced EGF-stimulated cell cycle entry by 44% and 69% in MCF-10A breast and RWPE-1 prostate cells, respectively. SEPW1 and EGF additively suppressed phosphorylation of Ser-33 in p53 and increased S-phase entry, suggesting at least part of EGF’s proliferative effect is due to suppression of p53 activation. Glutathione peroxidase depletion had opposite effects from SEPW1 depletion and partially rescued EGF insensitivity, activation of p53, and G1 arrest from SEPW1 depletion. Thus, the effects of SEPW1 depletion are not a result of loss of antioxidant protection. Because dysfunctions in the EGFR pathway drive development of many cancers, the involvement of SEPW1 may be related to the hypothesized increase in cancer risk associated with high dietary selenium intakes. Knowledge of the underlying mechanisms may reveal new therapeutic targets for cancer drug development.