Oncogene
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We have recently reported that Rituximab (anti-CD20) sensitizes drug-resistant 2F7 and 10C9 B Non-Hodgkin's lymphoma (NHL) cell lines to the apoptotic effects of various chemotherapeutic drugs by downregulation of IL-10 and Bcl-2 expression. The mechanism by which Rituximab induces downregulation of IL-10 was examined. We hypothesized that Rituximab may inhibit p38 MAPK activity that regulates IL-10 expression via Sp1. ⋯ Thus, altogether, these results demonstrate that signaling by Rituximab results in the inhibition of the p38MAPK pathway, which in turn inhibits the transcription of IL-10 via Sp1. Inhibition of the IL-10 autocrine/paracrine loop results in the inhibition of STAT3 activity and, consequently, inhibition of Bcl-2 expression and sensitization to drugs-apoptosis. Further, Rituximab-mediated signaling identifies several new intracellular targets in NHL that may be of potential therapeutic interest for the development of new drugs in the treatment of drug-refractory NHL tumor cells.
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The drs gene was originally isolated as a suppressor against v-src transformation. Expression of drs mRNA was markedly downregulated in a variety of human cancer cell lines and tissues, suggesting that the drs gene acts as a tumor suppressor. In this study, we found that ectopic expression of the Drs protein induced apoptosis in human cancer cell lines. ⋯ The release of cytochrome c from the mitochondria into the cytoplasm was not observed in apoptosis by drs, suggesting that the mitochondrial pathway does not mediate drs-induced apoptosis. Furthermore, we found that the Drs protein can interact with ASY/Nogo-B/RTN-x(S), an apoptosis-inducing protein localized in the endoplasmic reticulum, and that coexpression of these genes increased the efficiency of apoptosis. These results indicated that Drs induces apoptosis by a novel pathway mediated by ASY/Nogo-B/RTN-x(S), caspase-12, -9, and -3.