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Thioredoxin, a Gene Found Overexpressed in Human Cancer, Inhibits Apoptosis in Vitro and in Vivo¹

Arizona Cancer Center [A. B., G. P.], Department of Microbiology and Immunology and Arizona Research Laboratories [C. M. P.], and Department of Pathology [M. M. B.], University of Arizona, Health Sciences Center, Tucson, Arizona 85724

The redox protein thioredoxin plays an important role in controlling cancer cell growth through regulation of DNA synthesis and transcription factor activity. Thioredoxin is overexpressed by a number of human primary cancers and its expression is decreased during dexamethasone-induced apoptosis of mouse WEHI7.2 thymoma cells. We examined the ability of WEHI7.2 cells stably transfected with human thioredoxin cDNA showing increased levels of cytoplasmic thioredoxin to undergo apoptosis in vitro and in vivo. The cells were protected from apoptosis induced by dexamethasone, staurosporine, etoposide, and thapsigargin, but not by N-acetyl-sphingosine. When inoculated into severe combined immunodeficient mice, the trx-transfected cells formed tumors that showed increased growth compared to wild-type, as well as bcl-2-transfected, WEHI7.2 cells. The trx- and bcl-2-transfected cell tumors both showed less spontaneous apoptosis than tumors formed by the wild-type cells. Unlike tumors formed by the wild-type and bcl-2-transfected WEHI7.2 cells, trx-transfected cell tumors did not show growth inhibition upon treatment with dexamethasone. This study suggests that increased thioredoxin expression in human cancers may result in an increased tumor growth through inhibition of spontaneous apoptosis and a decrease in the sensitivity of the tumor to drug-induced apoptosis.

¹ This work was supported by NIH Grant CA48725 (to G. P.). A. B. was partly supported by a grant from the American Foundation for Pharmaceutical Education.

² To whom requests for reprints should be addressed, at Arizona Cancer Center, University of Arizona, 1515 North Campbell Avenue, Tucson, AZ 85724-5024. Phone: (520) 626-6408; Fax: (520) 626-4848; E-mail: gpowis@azcc.arizona.edu.

Received 2/ 7/97. Accepted 9/17/97.

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