Targeting the translational machinery as a novel treatment strategy for non-Hodgkin lymphoma

Abstract

Non-Hodgkin lymphoma (NHL) is a heterogeneous group of B-cell and T-cell malignancies, which originate in tissues of the lymph system. According to the National Cancer Institute, non-Hodgkin lymphoma is the fifth most diagnosed cancer in the country. Diffuse large B-cell lymphoma is the most common of the NHL, accounting for approximately 40% of all NHL. Although the transcriptional mechanisms involving c-MYC and BCL6 have been extensively studied in DLBCL, little is known about the role of post-transcriptional mechanisms involved in lymphomagenesis. The dysregulation of protein synthesis evident in the transformed phenotype has opened up a burgeoning field of research in cancer biology. Translation initiation has recently been shown to be a common downstream target of signal transduction pathways deregulated in cancer and initiated by mutated/overexpressed oncogenes and tumor suppressors. The overexpression and/or activation of proteins involved in translation initiation such as eIF4E, mTOR and eIF4G have been shown to induce a malignant phenotype. Therefore, understanding the mechanisms that control protein synthesis is emerging as an exciting new research area with significant potential for developing innovative therapies. We demonstrated that the oncogene MCT-1 is highly expressed in 85% of primary DLBCL samples. Disruption of MCT-1 function by either a dominant negative or inhibitory RNA (RNAi) attenuated the malignant phenotype through a mechanism involving the modulation of the translational profile present in the lymphoma. Microarray analysis of actively translating polysomes demonstrated that inhibition of MCT-1 led to an increase in the translation of messages with tumor suppressor functions and a decrease in the translation of oncogenic messages. The inverse correlation between chronic alcohol consumption and incidence of NHL has been observed in multiple epidemiological studies. We demonstrated that ethanol inhibits mammalian target of rapamycin (mTOR) signaling, which resulted in a decrease in cap-dependent translation. Microarray analysis of mRNA bound to actively translating ribosomes demonstrated those messages most significantly repressed encode the translational machinery. Further, chronic ethanol exposure resulted in diminished tumor formation in a pre-clinical human lymphoma xenograft model. Deregulated protein synthesis may be achieved through the overexpression of ribosomal proteins. We demonstrated that ribosomal protein S6 (RPS6) is highly expressed in primary DLBCL samples. Genetic modulation of RPS6 protein levels with specifically targeted short hairpin RNA (shRNA) lead to an increase in the apoptotic population of cells compared to control shRNA. We also demonstrated that RPS6 regulates the translation of messages containing a 5' terminal oligopyrimidine (5' TOP) tract, which encode the translational machinery. These findings are significant for the clinical setting as specifically targeting molecules upon which DLBCL depends for the survival of the disease may achieve more significant patient responses. Therefore we believe that targeting the translational machinery may constitute a novel therapeutic approach in the treatment of cancer.