Syk-dependent mTOR activation in follicular lymphoma cells.
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.
Leseux
Ludivine
L
INSERM U563-Centre de Physiopathologie Toulouse Purpan (CPTP), Département d'Oncogenèse et Signalisation dans les Cellules Hématopoïétiques, Centre Hospitalier Universitaire (CHU) Purpan-BP3028, Toulouse, France.
Hamdi
Safouane M
SM
Al Saati
Talal
T
Capilla
Florence
F
Recher
Christian
C
Laurent
Guy
G
Bezombes
Christine
C
D002051:Burkitt Lymphoma / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D045744:Cell Line, Tumor; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D008198:Lymph Nodes / Q000378:metabolism / Q000473:pathology; D016393:Lymphoma, B-Cell / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D008224:Lymphoma, Follicular / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D020522:Lymphoma, Mantle-Cell / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D009363:Neoplasm Proteins / Q000378:metabolism*; D014066:Palatine Tonsil / Q000201:enzymology / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010739:Phospholipase D / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics / Q000494:pharmacology; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013267:Stilbenes / Q000494:pharmacology; D000072377:Syk Kinase; D058570:TOR Serine-Threonine Kinases
D047908:Intracellular Signaling Peptides and Proteins; D009363:Neoplasm Proteins; D019869:Phosphatidylinositol 3-Kinases; D010739:Phospholipase D; D011494:Protein Kinases; D011505:Protein-Tyrosine Kinases; D034741:RNA, Small Interfering; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D013267:Stilbenes; D000072377:Syk Kinase; D058570:TOR Serine-Threonine Kinases; C041525:3,3',4,5'-tetrahydroxystilbene; C546842:MTOR protein, human; C000606896:SYK protein, human