Examination of anticancer mechanisms in ras‐induced cancer cells by targeting thioredoxin reductase 1 knockdown

Abstract

Thioredoxin reductase 1 (TR1) is a major antioxidant and redox regulator in mammals. This selenium-containing oxidoreductase is enriched in many malignant cells and has been proposed as a target for cancer therapy. To assess the role of TR1 in the malignancy process, we used RNAi technology to knockdown its expression in a lung cancer cell line whereby reversing many of the malignant phenotypes (Yoo et al. JBC, 281: , 2006). To further elucidate the role of TR1 in cancer therapy, we targeted the removal of TR1 expression in DT cells that overexpress oncogenic ras and manifest numerous malignant phenotypes. We found that DT cells overexpress TR1 compared with its normal control, NIH3T3 cells. Knockdown of TR1 resulted in a significant reduction in its anchorage-independent growth properties. We examined gene expression in normal (NIH3T3), cancer (DT) and TR1 knockdown (DT/siTR1) cells by microarray analysis and found several mRNAs that are characteristically elevated in cancer cells were down-regulated in the DT/siTR cells. We are expanding these findings and examining additional properties of DT/siTR1 cells to better evaluate TR1 as a target for cancer therapy. This research was supported by the Intramural Research Program of the NIH, NCI, CCR.