Rituximab-Induced Inhibition of YY1 and Bcl-xL Expression in Ramos Non-Hodgkin’s Lymphoma Cell Line via Inhibition of NF-κB Activity: Role of YY1 and Bcl-xL in Fas Resistance and Chemoresistance, Respectively

Abstract

Rituximab treatment of B non-Hodgkin’s lymphoma (NHL) cell lines inhibits the constitutive NF-κB activity and results in the sensitization of tumor cells to both chemotherapy and Fas-induced apoptosis. Cells expressing dominant active IκB or treated with NF-κB-specific inhibitors were sensitive to both drugs and Fas agonist mAb (CH-11)-induced apoptosis. Down-regulation of Bcl-xL expression via inhibition of NF-κB activity correlated with chemosensitivity. The direct role of Bcl-xL in chemoresistance was demonstrated by the use of Bcl-xL-overexpressing Ramos cells, Ramos hemagglutinin (HA)-Bcl-x, which were not sensitized by rituximab to drug-induced apoptosis. However, inhibition of Bcl-xL in Ramos HA-Bcl-x resulted in sensitization to drug-induced apoptosis. The role of Bcl-xL expression in the regulation of Fas resistance was not apparent; Ramos HA-Bcl-x cells were as sensitive as the wild type to CH-11-induced apoptosis. Several lines of evidence support the direct role of the transcription repressor yin-yang 1 (YY1) in the regulation of resistance to CH-11-induced apoptosis. Inhibition of YY1 activity by either rituximab or the NO donor DETANONOate or after transfection with YY1 small interfering RNA resulted in up-regulation of Fas expression and sensitization to CH-11-induced apoptosis. These findings suggest two mechanisms underlying the chemosensitization and immunosensitization of B-NHL cells by rituximab via inhibition of NF-κB. The regulation of chemoresistance by NF-κB is mediated via Bcl-xL expression, whereas the regulation of Fas resistance by NF-κB is mediated via YY1 expression and activity. The potential clinical significance of these findings is discussed.

Tumor-suppressing Function of Caspase-2 Requires Catalytic Site Cys-320 and Site Ser-139 in Mice

“…Resistance to apoptosis accompanied by uncontrollable cell division could promote growth of tumor mass in the nude mice. This working model is also supported by the knowledge that a G 2 /M checkpoint defect promotes tumorigenesis (3) and that there is close association of up-regulation of three such antiapoptotic proteins, Bcl-xL, XIAP, and cIAP2, with constitutive activation of NF-B and resistance to apoptosis in a variety of human malignancies (45)(46)(47)(48)(49)(50).…”

Chemotherapeutic drugs sensitize cancer cells to TRAIL-mediated apoptosis: up-regulation of DR5 and inhibition of Yin Yang 1

“…In previous findings, we have reported that Fas expression is negatively regulated by the transcription repressor YY1 via binding of YY1 to the silencer region of the Fas promoter (19). We have also reported that inhibition of NF-nB correlated with inhibition of YY1 (20). Because there is a putative binding site for YY1 in the DR5 promoter, we hypothesized that chemotherapeutic drugs may inhibit YY1 expression or its DNA-binding activity, resulting in up-regulation of DR5 expression and sensitization to TRAIL-induced apoptosis.…”

“…Consistent with our findings here, Palayoor et al (30) have reported that NF-nB is constitutively activated in the hormone-refractory prostate cancer cell lines PC-3 and DU145. The suppression of NFnB survival signaling by various agents has been shown to sensitize different neoplasms, including prostate tumors, to the antitumor effects of TRAIL (20,31) via several mechanisms (24,32,33). However, many antineoplastic agents, including anthracyclines, paclitaxel, and Vinca alkaloids, have been shown to induce NF-nB activation in human lung adenocarcinoma and other cell lines mainly via activation of protein kinase C, resulting in InBa degradation (34 -36).…”

“…Electrophoretic Mobility Shift Assay For determination of YY1 DNA-binding activity before and after treatment, nuclear extracts from 18 h CDDPtreated cells were prepared and analyzed by electrophoretic mobility shift assay as described previously (20).…”

Mechanisms of nitric oxide-mediated inhibition of EMT in cancer

“…We have reported that treatment of prostate tumor and non-Hodgkin's B cell lymphoma (B-NHL) cell lines with DETANONOate reduced the NFκB DNA-binding activity attributed to S-nitrosylation of the NFκB p50 subunit by NO. 33,42,43 The above observations suggest that NO is a potent NFκB inhibitor and that DETANONOate mediates its anti-metastatic properties, in part, via suppression of NFκB signaling.…”