Rapamycin can restore the negative regulatory function of transforming growth factor beta 1 in high grade lymphomas

A. Sebestyén, Ágnes Márk, Melinda Hajdu, Noémi Nagy, Anna Molnár, Gyula Végso, G. Barna, L. Kópper

Research output: Article

9 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)219-224
Number of pages6
JournalCytokine
Volume73
Issue number2
DOIs
Publication statusPublished - jún. 1 2015

Fingerprint

Sirolimus
Transforming Growth Factor beta
Non-Hodgkin's Lymphoma
Apoptosis
Lymphoma
Ribosomal Protein S6
Cells
Lymphocytes
Ribosomal Protein S6 Kinases
70-kDa Ribosomal Protein S6 Kinases
Protein Phosphatase 2
Phosphorylation
Caspase Inhibitors
Cell growth
B-Cell Lymphoma
Cell- and Tissue-Based Therapy
Caspases
Small Interfering RNA
Machinery
Phosphotransferases

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy
  • Hematology
  • Biochemistry
  • Molecular Biology

Cite this

Rapamycin can restore the negative regulatory function of transforming growth factor beta 1 in high grade lymphomas. / Sebestyén, A.; Márk, Ágnes; Hajdu, Melinda; Nagy, Noémi; Molnár, Anna; Végso, Gyula; Barna, G.; Kópper, L.

In: Cytokine, Vol. 73, No. 2, 01.06.2015, p. 219-224.

Research output: Article

Sebestyén, A. ; Márk, Ágnes ; Hajdu, Melinda ; Nagy, Noémi ; Molnár, Anna ; Végso, Gyula ; Barna, G. ; Kópper, L. / Rapamycin can restore the negative regulatory function of transforming growth factor beta 1 in high grade lymphomas. In: Cytokine. 2015 ; Vol. 73, No. 2. pp. 219-224.
@article{68286b1452464e1887ff59b6eb7d0b4f,
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.",
keywords = "Apoptosis, Lymphoma, MTOR, Rapamycin, TGF-β",
author = "A. Sebesty{\'e}n and {\'A}gnes M{\'a}rk and Melinda Hajdu and No{\'e}mi Nagy and Anna Moln{\'a}r and Gyula V{\'e}gso and G. Barna and L. K{\'o}pper",
year = "2015",
month = "6",
day = "1",
doi = "10.1016/j.cyto.2015.02.024",
language = "English",
volume = "73",
pages = "219--224",
journal = "Cytokine",
issn = "1043-4666",
publisher = "Academic Press Inc.",
number = "2",

}

TY - JOUR

T1 - Rapamycin can restore the negative regulatory function of transforming growth factor beta 1 in high grade lymphomas

AU - Sebestyén, A.

AU - Márk, Ágnes

AU - Hajdu, Melinda

AU - Nagy, Noémi

AU - Molnár, Anna

AU - Végso, Gyula

AU - Barna, G.

AU - Kópper, L.

PY - 2015/6/1

Y1 - 2015/6/1

N2 - 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.

AB - 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.

KW - Apoptosis

KW - Lymphoma

KW - MTOR

KW - Rapamycin

KW - TGF-β

UR - http://www.scopus.com/inward/record.url?scp=84924992147&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84924992147&partnerID=8YFLogxK

U2 - 10.1016/j.cyto.2015.02.024

DO - 10.1016/j.cyto.2015.02.024

M3 - Article

C2 - 25794661

AN - SCOPUS:84924992147

VL - 73

SP - 219

EP - 224

JO - Cytokine

JF - Cytokine

SN - 1043-4666

IS - 2

ER -