Secretion of thioredoxin enhances cellular resistance to cis-diamminedichloroplatinum (II)

Thioredoxin (TRX) is a redox-active protein induced by a variety of stress and secreted from cells. Collecting evidence revealed that extracellular TRX shows cytokine- and chemokine-like activities. In the present study, we studied the role of secreted TRX on cellular resistance to cis-diamminedichloroplatinum (II) (CDDP). The CDDP-resistant variants of HeLa cells not only have enhanced expression of intracellular TRX, but also show increased secretion of TRX into the culture medium, compared to the parental cells. The CDDP-resistant cells also exhibit an enhanced L-cystine uptake capability, which results in a significant increase in the intracellular sulfhydryl content, including glutathione (GSH). Exogenous administration of recombinant TRX (rTRX) increases cellular resistance to CDDP and augments the L-cystine uptake in the parental HeLa cells. Moreover, depletion of L-cystine from the culture medium or combined treatment with L-cystine uptake inhibitors increases cellular sensitivity to CDDP in the CDDP-resistant cells. These findings suggest that secreted TRX may play an important role in the acquisition of cellular CDDP resistance through enhancement of the L-cystine uptake activity, and that the L-cystine transport system, as well as the TRX system, may be a novel therapeutic target in CDDP-resistant cancer cells.