Targeting thioredoxin reductase 1 reduction in cancer cells inhibits self-sufficient growth and DNA replication.
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 alpha, an enzyme important in DNA replication. These observations provide evidence that TR1 is critical for self-sufficiency in growth signals of malignant cells, that TR1 acts largely as a pro-cancer protein and it is indeed a primary target in cancer therapy.
Yoo
Min-Hyuk
MH
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.
Xu
Xue-Ming
XM
Carlson
Bradley A
BA
Patterson
Andrew D
AD
Gladyshev
Vadim N
VN
Hatfield
Dolph L
DL
D000362:Agar / Q000737:chemistry; D000818:Animals; D000975:Antioxidants / Q000737:chemistry; D002453:Cell Cycle; D045744:Cell Line, Tumor; D004261:DNA Replication; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D051379:Mice; D008954:Models, Biological; D041681:NIH 3T3 Cells; D009369:Neoplasms / Q000378:metabolism*; D010641:Phenotype; D051140:Selenoproteins / Q000737:chemistry; D054481:Thioredoxin Reductase 1 / Q000096:biosynthesis*
D000975:Antioxidants; D051140:Selenoproteins; D000362:Agar; D054481:Thioredoxin Reductase 1