stilbenes and Lymphoma--Follicular

The mammalian target of rapamycin (mTOR) is emerging as a promising target for antitumor therapy. However, the mechanism that contributes to its regulation in B lymphomas remains unknown. This study shows that in follicular lymphoma (FL) cells, mTOR is active because the cells displayed rapamycin-sensitive phosphorylation of p70S6 kinase and 4E-BP1. Moreover, immunohistochemistry applied on lymph node tissue sections obtained from patients with FL revealed that, in most cases, p70S6 kinase was highly phosphorylated compared to normal tonsillar tissue. In FL cells, mTOR was under control of both phospholipase D (PLD) and phosphatidylinositol 3-kinase (PI3K). Moreover, we demonstrated that Syk plays a central role in mTOR activation because we found that both expression and activity are elevated compared to normal or chronic lymphocytic leukemia B cells. We also provide evidence that Syk operates through PLD- and PI3K-independent pathways. Finally, Syk inhibition by piceatannol or by siRNA plasmids resulted in a potent inhibition of mTOR activity in FL cells, as well as in mantle cell lymphoma, Burkitt lymphoma, and diffuse large B-cell lymphoma. These findings suggest that the Syk-mTOR pathway has a critical function in FL survival, and therefore, that Syk could be a promising new target for B-lymphoma therapy.

Topics: Burkitt Lymphoma; Cell Line, Tumor; Enzyme Activation; Humans; Intracellular Signaling Peptides and Proteins; Leukemia, Lymphocytic, Chronic, B-Cell; Lymph Nodes; Lymphoma, B-Cell; Lymphoma, Follicular; Lymphoma, Mantle-Cell; Neoplasm Proteins; Palatine Tonsil; Phosphatidylinositol 3-Kinases; Phospholipase D; Protein Kinases; Protein-Tyrosine Kinases; Ribosomal Protein S6 Kinases, 70-kDa; RNA, Small Interfering; Signal Transduction; Stilbenes; Syk Kinase; TOR Serine-Threonine Kinases

Resveratrol is a polyphenolic compound that exhibits anti-proliferative and anti-inflammatory activities. BCL6, a transcriptional repressor frequently translocated in lymphomas, including diffuse large B-cell lymphoma (DLBCL) and transformed follicular lymphoma (FL), regulates germinal center B-cell differentiation. We report herein that resveratrol treatment of human LY8 follicular lymphoma cells leads to an accumulation of LY8 cell in G0/G1 phase and apoptosis. Resveratrol decreased the expression of BCL6 protein, concomitant with the increased expression of several BCL6 regulated gene products, including p27, p53 and CD69. In addition, resveratrol reduces Myc expression in LY8 cells. These results demonstrate for the first time that resveratrol inhibits a BCL6-linked pathway and suggest that loss of BCL6 expression may represent a key event underlying the anti-proliferative activities of resveratrol on LY8 cells. The use of resveratrol to treat aggressive lymphomas with BCL6 and/or MYC translocations may prove useful as an effective therapy.

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Cell Cycle; Cell Line, Transformed; DNA-Binding Proteins; Genes, myc; Genes, p53; Humans; Lymphoma, B-Cell; Lymphoma, Follicular; MAP Kinase Signaling System; Mitogen-Activated Protein Kinase Kinases; Proliferating Cell Nuclear Antigen; Proto-Oncogene Proteins c-bcl-6; Resveratrol; Stilbenes