title: Rapamycin can restore the negative regulatory function of transforming growth factor beta 1 in high grade lymphomas.
abstract: TGF-β1 (transforming growth factor beta 1) is a negative regulator of lymphocytes, inhibiting proliferation and switching on the apoptotic program in normal lymphoid cells. Lymphoma cells often lose their sensitivity to proapoptotic/anti-proliferative regulators such as TGF-β1. Rapamycin can influence both mTOR (mammalian target of rapamycin) and TGF-β signaling, and through these pathways it is able to enhance TGF-β induced anti-proliferative and apoptotic responses. In the present work we investigated the effect of rapamycin and TGF-β1 combination on cell growth and on TGF-β and mTOR signalling events in lymphoma cells. Rapamycin, an inhibitor of mTORC1 (mTOR complex 1) did not elicit apoptosis in lymphoma cells; however, the combination of rapamycin with exogenous TGF-β1 induced apoptosis and restored TGF-β1 dependent apoptotic machinery in several lymphoma cell lines with reduced TGF-β sensitivity in vitro. In parallel, the phosphorylation of p70 ribosomal S6 kinase (p70S6K) and ribosomal S6 protein, targets of mTORC1, was completely eliminated. Knockdown of Smad signalling by Smad4 siRNA had no influence on apoptosis induced by the rapamycin+TGF-β1, suggesting that this effect is independent of Smad signalling. However, apoptosis induction was dependent on early protein phosphatase 2A (PP2A) activity, and in part on caspases. Rapamycin+TGF-β1 induced apoptosis was not completely eliminated by a caspase inhibitor. These results suggest that high mTOR activity contributes to TGF-β resistance and lowering mTORC1 kinase activity may provide a tool in high grade B-cell lymphoma therapy by restoring the sensitivity to normally available regulators such as TGF-β1.
authors: Semmelweis University, 1st Department of Pathology and Experimental Cancer Research, Budapest 1085, Üllői út 26., Hungary; Tumor Progression Research Group of Joint Research Organization of the Hungarian Academy of Sciences and Semmelweis University, Budapest 1085, Üllői út 26, Hungary. Electronic address: anna@korb1.sote.hu.
authors: Anna
authors: A
authors: Sebestyén
authors: Semmelweis University, 1st Department of Pathology and Experimental Cancer Research, Budapest 1085, Üllői út 26., Hungary. Electronic address: markagi@korb1.sote.hu.
authors: Ágnes
authors: Á
authors: Márk
authors: Semmelweis University, 1st Department of Pathology and Experimental Cancer Research, Budapest 1085, Üllői út 26., Hungary. Electronic address: melindahajdu@gmail.com.
authors: Melinda
authors: M
authors: Hajdu
authors: Semmelweis University, 1st Department of Pathology and Experimental Cancer Research, Budapest 1085, Üllői út 26., Hungary. Electronic address: n.noncsi@freemail.hu.
authors: Noémi
authors: N
authors: Nagy
authors: Semmelweis University, 1st Department of Pathology and Experimental Cancer Research, Budapest 1085, Üllői út 26., Hungary. Electronic address: molnar.anna.kutdiak@gmail.com.
authors: Anna
authors: A
authors: Molnár
authors: Semmelweis University, Department of Transplantation and Surgery, Budapest 1082, Baross u. 23, Hungary. Electronic address: vegso.gyula@med.semmelweis-univ.hu.
authors: Gyula
authors: G
authors: Végső
authors: Semmelweis University, 1st Department of Pathology and Experimental Cancer Research, Budapest 1085, Üllői út 26., Hungary. Electronic address: gbarna@korb1.sote.hu.
authors: Gábor
authors: G
authors: Barna
authors: Semmelweis University, 1st Department of Pathology and Experimental Cancer Research, Budapest 1085, Üllői út 26., Hungary. Electronic address: kopper@korb1.sote.hu.
authors: László
authors: L
authors: Kopper
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D008228:Lymphoma, Non-Hodgkin / Q000378:metabolism* / Q000473:pathology; D016513:Mice, SCID; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology*; D051901:Smad4 Protein / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D018125:Receptors, Transforming Growth Factor beta; D051901:Smad4 Protein; D053773:Transforming Growth Factor beta1; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; D020123:Sirolimus
keywords: Apoptosis; Lymphoma; Rapamycin; TGF-β; mTOR