Rapamycin can restore the negative regulatory function of transforming growth factor beta 1 in high grade lymphomas |
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| Affiliation: | 1. Semmelweis University, 1st Department of Pathology and Experimental Cancer Research, Budapest 1085, Üllői út 26., Hungary;2. Tumor Progression Research Group of Joint Research Organization of the Hungarian Academy of Sciences and Semmelweis University, Budapest 1085, Üllői út 26, Hungary;3. Semmelweis University, Department of Transplantation and Surgery, Budapest 1082, Baross u. 23, Hungary;1. Magee-Womens Research Institute, Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh, 204 Craft Avenue, Pittsburgh, PA, 15213, USA;2. Department of Microbiology and Molecular Genetics, University of Pittsburgh, Pittsburgh, PA, USA;1. Department of Anatomy, Histology and Embryology, Faculty of Medicine, Semmelweis University, Budapest, Hungary;2. Department of Medical Biology, Faculty of Medicine, University of Szeged, Hungary;3. Department of Pathology and Experimental Cancer Research, Faculty of Medicine, Budapest, Hungary;1. Department of Radiology and Nuclear Medicine, VU University Medical Center, de Boelelaan 1117, 1081 HV, Amsterdam 1059 SX, The Netherlands.;2. Department of Otolaryngology Head and Neck Surgery, VU University Medical Center, de Boelelaan 1117, 1081 HV, Amsterdam 1059 SX, The Netherlands.;1. Division of Gastroenterology and Hepatology, East Carolina University, Greenville, Chapel Hill North Carolina, USA;2. Division of Gastroenterology and Hepatology, University of North Carolina, Chapel Hill, Chapel Hill North Carolina, USA;1. Department of Medical Oncology, Catalan Institute of Oncology (ICO), IDIBELL, L’Hospitalet de Llobregat, Barcelona, Spain;2. Cancer Epidemiology Research Program, Catalan Institute of Oncology (ICO), IDIBELL, L’Hospitalet de Llobregat, Barcelona, Spain;3. University of Barcelona, Barcelona, Spain;4. Head and Neck Medical Oncology Department, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy;5. Department of Pathology, The Ohio State University Medical Center, Columbus, OH, United States;6. Department of Medicine, The Ohio State University, Columbus, OH, United States;7. Department of Otolaryngology, The Ohio State University Medical Center, Columbus, OH, United States;1. Department of Orthopedics, The Second Xiangya Hospital Affiliated with Central South University, Changsha 410011, China;2. Department of Orthopedics, Clinical medical college of Yangzhou University, Subei People’s Hospital of Jiangsu Province, Yangzhou 225001, China |
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| 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. |
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| Keywords: | Rapamycin TGF-β mTOR Apoptosis Lymphoma |
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