Submitted to: Biological Trace Element Research
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 3/16/2009
Publication Date: 4/22/2009
Citation: Hawkes, W.C., Wang, T.T., Alkan, Z., Richter, D., Dawson, K. 2009. Selenoprotein W Modulates Control of Cell Cycle Entry. Humana Press Inc, Biological Trace Element Research. 131:229-244.
Interpretive Summary: Selenium is an essential nutrient required in trace amounts in the human diet. Selenium’s potential for fighting cancer was first recognized over 90 years ago. Even so, we still do not understand how selenium works. We undertook this study to identify the cellular targets of dietary selenium for prevention of breast and prostate cancers. When human breast and prostate cells were exposed to low levels of selenium in its natural forms – like those found in blood serum – selenoprotein W (SEPW1) was the only gene affected. Cells with decreased SEPW1 grew slower due to a delay in re-entering the cell cycle. SEPW1 was down-regulated as soon as cells re-entered the cell cycle, similar to checkpoint proteins. Cell cycle entry is a major site of dysfunction in cancer and accounts for much of the uncontrolled growth of tumors. Most tumor suppressor genes as well as most oncogenes target this part of the cell cycle. Understanding the role of selenium in controlling cell cycle entry could lead to new approaches for the nutritional prevention of breast and prostate cancers.
Technical Abstract: The cancer-protective properties of selenium (Se) have been recognized for over 90 years, yet the mechanisms remain obscure. The present study was conducted to identify targets of supplemental Se provided to cultured human cells in physiologically relevant doses and forms. Breast and prostate epithelial cells were supplemented with Se provided as 100 nM sodium selenite or high-Se serum and gene expression was profiled with DNA microarrays. Pure sodium selenite affected expression of 560 genes in breast cells, including 60 associated with the cell cycle (p=2.8 x 10-16). Selenoprotein W (SEPW1) was the only selenoprotein mRNA increased by both sodium selenite (specific) and high-Se serum (physiologic). SEPW1 siRNA delayed G1-phase progression and increased G1-phase gene transcripts, while decreasing S-phase and G2/M-phase gene transcripts, indicating the cell cycle was interrupted at the G1/S transition. SEPW1 mRNA levels were maximal during G1-phase, dropped rapidly during early S-phase and rebounded after G2/M-phase. SEPW1-underexpressing prostate cells had increased mRNA for BCL2, which induces G1 arrest, and decreased mRNA for RBBP8 and KPNA2, which modulate the Rb/p53 checkpoint pathway. These results suggest SEPW1 and the G1/S transition are physiological targets of supplemental Se in breast and prostate epithelial cells. A role for Se in modulating control of cell cycle entry may lead to potential new mechanisms of cancer prevention via Se supplementation.