targeting thioredoxin reductase 1 reduction in cancer cells inhibits self-sufficient growth and dna replication针对硫氧还蛋白还原酶1减少癌细胞抑制自给自足的生长和dna复制.pdfVIP

Targeting Thioredoxin Reductase 1 Reduction in Cancer Cells Inhibits Self-Sufficient Growth and DNA Replication 1 1 1 1¤ 2 1 Min-Hyuk Yoo , Xue-Ming Xu , Bradley A. Carlson , Andrew D. Patterson , Vadim N. Gladyshev , Dolph L. Hatfield * 1 Molecular Biology of Selenium Section, Laboratory of Cancer Prevention, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America, 2 Department of Biochemistry, University of Nebraska, Lincoln, Nebraska, United States of America Thioredoxin reductase 1 (TR1) is a major redox regulator in mammalian cells. As an important antioxidant selenoprotein, TR1 is thought to participate in cancer prevention, but is also known to be over-expressed in many cancer cells. Numerous cancer drugs inhibit TR1, and this protein has been proposed as a target for cancer therapy. We previously reported that reduction of TR1 levels in cancer cells reversed many malignant characteristics suggesting that deficiency in TR1 function is antitumorigenic. The molecular basis for TR1’s role in cancer development, however, is not understood. Herein, we found that, among selenoproteins, TR1 is uniquely overexpressed in cancer cells and its knockdown in a mouse cancer cell line driven by oncogenic k-ras resulted in morphological changes characteristic of parental (normal) cells, without significant effect on cell growth under normal growth conditions. When grown in serum-deficient medium, TR1 deficient cancer cells lose self-sufficiency of growth, manifest a defective progression in their S phase and a decreased expression of DNA polymerase a, an enzyme important in DNA replication. These observations provide evide