Abstract
A majority of lymphomas are derived from B cells and novel treatments are required to treat refractory disease. Neurotransmitters such as serotonin and dopamine influence activation of B cells and the effects of a selective serotonin 1A receptor (5HT1A) antagonist on growth of a number of B cell-derived lymphoma cell lines were investigated. We confirmed the expression of 5HT1A in human lymphoma tissue and in several well-defined experimental cell lines. We discovered that the pharmacological inhibition of 5HT1A led to the reduced proliferation of B cell-derived lymphoma cell lines together with DNA damage, ROS-independent caspase activation and apoptosis in a large fraction of cells. Residual live cells were found ‘locked’ in a non-proliferative state in which a selective transcriptional and translational shutdown of genes important for cell proliferation and metabolism occurred (e.g., AKT, GSK-3β, cMYC and p53). Strikingly, inhibition of 5HT1A regulated mitochondrial activity through a rapid reduction of mitochondrial membrane potential and reducing dehydrogenase activity. Collectively, our data suggest 5HT1A antagonism as a novel adjuvant to established cancer treatment regimens to further inhibit lymphoma growth.
Highlights
B cell lymphomas represent a heterogeneous group of genetically, phenotypically and clinically distinct malignancies
Using RNA extraction and Quantitative real time PCR (rtqPCR) and western blot analysis, we demonstrated 5HT1A mRNA (Fig. 1b) and protein expression (Fig. 1c and Supplementary Fig. S1) in cell lines derived from Burkitt lymphomas (BL), diffuse large B cell lymphomas (DLBCL), chronic lymphocytic leukemia and mantle cell lymphoma
We investigated the selective antagonism of 5HT1A receptors to prevent proliferation of B cell-derived lymphoma cell lines and characterized key molecular and cellular events involved
Summary
B cell lymphomas represent a heterogeneous group of genetically, phenotypically and clinically distinct malignancies. The oncogenic transformation of B cells occurs during the germinal center reaction and gives rise to a number of lymphoma types, including diffuse large B cell lymphomas (DLBCL), Burkitt lymphomas (BL) or follicular lymphomas[1,2,3] Both DLBCL and BL have very high proliferation indices in which prompt diagnosis followed by an immediate start of therapy is critical for a positive clinical outcome[4]. A number of serotonin receptors and dopamine receptors are expressed by B cells and have been reported to play an important role in activation and proliferation of these, in vitro[15,16] This indicates a potential role of neurotransmitters for direct regulation of T cell-dependent B cell activation in the germinal center[15]. We investigate the potential of a selective serotonin receptor (5HT1A) antagonist to influence the proliferation and survival of B cell-derived lymphomas, and characterize key cellular and molecular pathways affected by treatment
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