Abstract
Primary effusion lymphoma (PEL) is defined as a rare subtype of non-Hodgkin's B-cell lymphoma which is caused by Kaposi's sarcoma-associated herpesvirus (KSHV) in immunosuppressed patients. PEL is an aggressive lymphoma and is frequently resistant to conventional chemotherapies. Therefore, it is critical to investigate novel therapeutic options for PEL. Capsaicin is a pungent component of chili pepper and possesses unique pharmacological effects, such as pain relief, anti-microbial and anti-cancer properties. Here, we demonstrate that capsaicin markedly inhibited the growth of KSHV latently infected PEL cells by inhibiting ERK, p38 MAPK and expression hIL-6, which are known to contribute to PEL growth and survival. The underlying mechanism of action by capsaicin was through the inhibition of ERK and p38 MAPK phosphorylation and signaling that affected hIL-6 expression. As a result, capsaicin induced apoptosis in PEL cells in a caspase-9 dependent manner. In line with these results, ERK (U0126) and p38 MAPK (SB203580) specific signaling inhibitors suppressed hIL-6 expression and attenuated cell growth in PEL cells. Furthermore, the addition of hIL-6 neutralizing antibody to culture medium suppressed the growth of PEL cells. We also demonstrate that capsaicin suppressed PEL cell growth in the absence of nascent viral replication. Finally, we confirmed ex vivo treatment of capsaicin attenuated PEL development in SCID mice. Taken together, capsaicin could represent a lead compound for PEL therapy without the risk of de novo KSHV infection.
Highlights
Primary effusion lymphoma (PEL) is classified as non-Hodgkin’s B-cell lymphoma when it develops in immunocompromised patients, such as those with acquired immune deficiency syndrome (AIDS) patients, and those taking immunosuppressant drugs after having undergone organ transplantation [1, 2]
We discovered that capsaicin has preferential cytotoxic activity against PEL to induce apoptosis compared with Kaposi’s sarcoma-associated herpesvirus (KSHV)-uninfected B-lymphoma cells
KSHV constitutively promotes extracellular signal-regulated kinase (ERK) and p38 p38 mitogen-activated protein kinase (MAPK) signaling and human interleukine-6 (hIL-6) expression in PEL cells, which might be related with higher sensitivity of PEL cells to capsaicin
Summary
Primary effusion lymphoma (PEL) is classified as non-Hodgkin’s B-cell lymphoma when it develops in immunocompromised patients, such as those with acquired immune deficiency syndrome (AIDS) patients, and those taking immunosuppressant drugs after having undergone organ transplantation [1, 2]. In KSHV-infected cells including PEL cells, KSHV expresses LANA, viral FLIP, microRNAs, and small amounts of viral interleukin 6 (vIL-6) and viral IRFs (vIRFs), all of which strongly contribute to persistent infection or exert a malignant phenotype [4,5,6] These viral transcripts utilize and mimic cellular signaling, including NFκB, Wnt, p53, mitogen-activated protein kinases (MAPKs) and cytokine signaling. These KSHV-mediated disruptions dysregulate proliferation, apoptosis, immune escape and production of cytokines such as human interleukin 6 (hIL6), IL-10 and vascular endothelial growth factor (VEGF) [4, 7,8,9,10]. The phosphorylated (i.e., activated) ERK1/2 can phosphorylate p90RSK and promote cell proliferation, survival, and metastasis through targeted gene expression [14]. p38 MAPK is activated by cellular stress stimuli or cytokines and is associated with stress response, cytokine production, cell growth and apoptosis [15]. p38 MAPK and ERK signaling further correlate with the production of inflammatory cytokine hIL-6 [16,17,18,19,20,21], which enhances cell proliferation of B-cell lymphoma including PEL [4, 22,23,24]
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