CD26/Dipeptidyl Peptidase IV (DPPIV) Regulates p38 Phosphorylation and Topoisomerase II Alpha Expression in the B-Lymphoma Line Jiyoye, Associated with Enhanced In Vitro and In Vivo Sensitivity to Doxorubicin.

Abstract CD26 is a 110 kDa surface glycoprotein with diverse functional properties, including having a key role in normal T-cell biology, being a marker of aggressive disease for selected T-cell malignancies and being involved in the development of certain cancers. Its extracellular domain encodes a membrane-associated dipeptidyl peptidase IV (DPPIV) activity capable of processing biological factors to alter their functional profiles. We have shown previously that expression of CD26 on the T cell line Jurkat is associated with increased topoisomerase II alpha level and in vitro sensitivity to topoisomerase II inhibitors (Aytac U et al. Cancer Res61:7204, 2001; Aytac U et al. Br J Cancer88:455, 2003; Sato K et al. Br J Cancer89:1366, 2003). We now show that CD26 expression, particularly its DPPIV enzyme activity, on the B-lymphoma line Jiyoye results in increased topoisomerase II alpha level and in vitro sensitivity to doxorubicin-induced apoptosis. Examining the molecular mechanisms involved in CD26-associated signaling, our present findings also indicate that CD26/DPPIV expression on Jiyoye cells is associated with increased phosphorylation of p38 and its upstream regulators MKK3/6 and ASK1. Importantly, inhibition of p38 phosphorylation decreases topoisomerase II alpha expression, suggesting a role for p38 in the regulation of topoisomerase II alpha. Finally, studies using a SCID mouse xenograft model with CD26 Jiyoye transfectants show that CD26 expression is associated with enhanced survival following treatment with low doses of doxorubicin. In particular, treatment with low-dose doxorubicin of SCID mice injected with CD26-negative parental Jiyoye cells does not lead to a statistically significant survival advantage over those treated with saline. On the other hand, SCID mice injected with CD26 Jiyoye transfectants show significantly greater survival when treated with low-dose doxorubicin than with saline alone, indicating that CD26 presence renders tumor cells more sensitive to doxorubicin in an in vivo model. Our data thus characterize the biochemical linkage among CD26 and other key intracellular molecules, while demonstrating that CD26 may have a role in tumor sensitivity to antineoplastic agents targeting topoisomerase II alpha. In addition, our work suggests that CD26/DPPIV may be an appropriate target for therapy for selected hematological malignancies of both B- and T-cell lineages.