Chemosensitization of Drug-Resistant Ramos B-NHL to Drug-Induced Apoptosis: YY1 Expression Is Decreased in Response to Cytoskeletal-Interacting Drugs.

The transcription factor Yin Yang 1 (YY1) regulates cellular differentiation, hematopoiesis, response to apoptotic stimuli, pathogenesis of cancer and its increased expression is associated with inhibition of differentiation of progenitor cells. We and others have previously shown that expression levels of YY1 also correlate with drug sensitivity in cancer cells. A comparison between the wild type (wt) Ramos, with the recently generated rituximab-resistant Ramos (Ramos RR) clones, revealed that, unlike wt Ramos, Ramos RR1 cannot be chemosensitized by rituximab and exhibited higher drug resistance. Further, there was enhanced YY1 expression in Ramos RR1. We hypothesized that overexpression of YY1 may be, in part, responsible for drug-resistance in Ramos RR1 and its inhibition can reverse resistance. This study investigated whether the heightened expression of YY1 in Ramos RR1 cells can be reversed by a panel of drugs used in combination. Ramos and Ramos RR1 cells were treated with vincristine, VP-16, CDDP, and ADR, and the NF-κB inhibitors Bortezomib and DHMEQ. Treatment of Ramos RR1 with the NF-κB inhibitor, in combination with any of the above chemotherapeutic drugs, reversed the acquired drug-resistance and synergy was achieved. Noteworthy, in Ramos RR1 cells, only vincristine (or in combination with NF-κB inhibitors) significantly abrogated or diminished YY1 expression. Similarly, in the prostatic cell line PC-3, 2-methoxyestradiol, another cytoskeletal interacting drug, resulted in marked reduction of YY1 expression level and activity (assessed by a luciferase reporter assay). These results suggest that YY1 overexpression may regulate the resistance of B-NHL to a selected group of drugs but not all drugs. The studies also suggest that agents that can modulate YY1 expression/activity may be potential therapeutics when used in combination with chemotherapeutic drugs in the treatment of drug and rituximab-resistant B-NHL. Currently, we are examining potential mechanisms that underlie the downregulation of YY1 expression by vincristine and 2-methoxyestradiol.