Anti-lymphoma peptide is inspired by mapping a sequence of four amino acids of KRAI motif as nuclear localization signal of Crlz-1

Abstract

Peptides of Crlz-1 nuclear localization signal as mapped to be a short KRAI sequence inhibited the proliferation of germinal center-derived Ramos cells from Burkitt's lymphoma patient. This anti-proliferative effect was mechanistically explained by a cascade of the block of Crlz-1 nuclear movement and consequential failure of CBFβ nuclear mobilization, resulting in the absence of bound Runx/CBFβ heterodimer on the enhancer-promoter of the Bcl-6 GC master gene. As a consequence of this heterodimer absence, the Bcl-6 expression was abolished, leading to the down-regulation of cyclins D1-D3 and the up-regulation of IRF-4, Blimp-1, and IgJ genes. Furthermore, this peptide decreased the production of rRNA in these cells, indicating that the nuclear Crlz-1 as a UTP-3 constituent of ribosomal small subunit processome might be necessary to regulate the biogenesis and/or processing of rRNA, and thereby produce ribosomes necessary for their rapid proliferation. Surprisingly, the KRAI motif peptides had an intrinsic cell-membrane permeability by themselves, and therefore their anti-proliferative and anti-tumor effects were also demonstrated in both the cultured cells and Ramos-xenografted mice just by adding them directly to the culture media or injecting them into tail veins. This definitely paved the prospective road to developing a novel anti-cancer peptide drug against the germinal center-derived B cell lymphoma.