Abstract
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 α, 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.
Highlights
Dietary selenium has potent cancer prevention activity [1] and both selenium-containing proteins [2,3 and references therein] and low molecular weight selenium-containing compounds [2 and references therein] have been implicated in this activity
Thioredoxin reductase 1 (TR1) is overexpressed in many cancer cells [9,10,11,12] and its inhibition by a variety of potent cancer drugs altered cancer-related properties of numerous tumors and malignant cells suggesting that this enzyme is a target for cancer therapy [9,10,11,12,14,15]
DT cells, which encode oncogenic k-ras [17,18], and the parental NIH3T3 cells were labeled with 75Se and the resulting protein extracts electrophoresed to examine the levels of TR1 and other selenoproteins (Fig. 1A, upper left panel)
Summary
Dietary selenium has potent cancer prevention activity [1] and both selenium-containing proteins (selenoproteins) [2,3 and references therein] and low molecular weight selenium-containing compounds (selenocompounds) [2 and references therein] have been implicated in this activity. Thioredoxin reductase 1 (TR1) is one of 24 known selenoproteins in rodents [4], is a major antioxidant and redox regulator in mammalian cells [5,6 and references therein] and has an essential role in mammalian development [7]. This enzyme appears to have opposing effects in cancer development as it has been implicated in both cancer prevention [8] and cancer promotion [9,10,11,12]. TR1 is overexpressed in many cancer cells [9,10,11,12] and its inhibition by a variety of potent cancer drugs altered cancer-related properties of numerous tumors and malignant cells suggesting that this enzyme is a target for cancer therapy [9,10,11,12,14,15]
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