Hydrogen Sulfide Mediates Tumor Cell Resistance to Thioredoxin Inhibitor.

Thioredoxin (Trx) is a pro-oncogenic molecule that underlies tumor initiation, progression and chemo-resistance. PX-12, a Trx inhibitor, has been used to treat certain tumors. Currently, factors predicting tumor sensitivity to PX-12 are unclear. Given that hydrogen sulfide (HS), a gaseous bio-mediator, promotes Trx activity, we speculated that it might affect tumor response to PX-12. Here, we tested this possibility. Exposure of several different types of tumor cells to PX-12 caused cell death, which was reversely correlated with the levels of HS-synthesizing enzyme CSE and endogenous HS. Inhibition of CSE sensitized tumor cells to PX-12, whereas addition of exogenous HS elevated PX-12 resistance. Further experiments showed that HS abolished PX-12-mediated inhibition on Trx. Mechanistic analyses revealed that HS stimulated Trx activity. It promoted Trx from the oxidized to the reduced state. In addition, HS directly cleaved the disulfide bond in PX-12, causing PX-12 deactivation. Additional studies found that, besides Trx, PX-12 also interacted with the thiol residues of other proteins. Intriguingly, HS-mediated cell resistance to PX-12 could also be achieved through promotion of the thiol activity of these proteins. Addition of HS-modified protein into culture significantly enhanced cell resistance to PX-12, whereas blockade of extracellular sulfhydryl residues sensitized cells to PX-12. Collectively, our study revealed that HS mediated tumor cell resistance to PX-12 through multiple mechanisms involving induction of thiol activity in multiple proteins and direct inactivation of PX-12. HS could be used to predict tumor response to PX-12 and could be targeted to enhance the therapeutic efficacy of PX-12.