Activation of mammalian target of rapamycin signaling pathway contributes to tumor cell survival in anaplastic lymphoma kinase-positive anaplastic large cell lymphoma

Francisco Vega, L. Jeffrey Medeiros, Vasiliki Leventaki, Coralyn Atwell, Jeong Hee Cho, Ling Tian, Francois Xavier Claret, George Z. Rassidakis

Research output: Contribution to journalArticle

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Abstract

Anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma (ALCL) frequently carries the t(2;5)(p23;q35) resulting in aberrant expression of chimeric nucleophosmin-ALK. Previously, nucleophosmin-ALK has been shown to activate phosphatidylinositol 3-kinase (PI3K) and its downstream effector, the serine/threonine kinase AKT. In this study, we hypothesized that the mammalian target of rapamycin (mTOR) pathway, which functions downstream of AKT, mediates the oncogenic effects of activated PI3K/AKT in ALK+ ALCL. Here, we provide evidence that mTOR signaling phosphoproteins, including mTOR, eukaryotic initiation factor 4E-binding protein-1, p70S6K, and ribosomal protein S6, are highly phosphorylated in ALK+ ALCL cell lines and tumors. We also show that AKT activation contributes to mTOR phosphorylation, at least in part, as forced expression of constitutively active AKT by myristoylated AKT adenovirus results in increased phosphorylation of mTOR and its downstream effectors. Conversely, inhibition of AKT expression or activity results in decreased mTOR phosphorylation. In addition, pharmacologic inhibition of PI3K/AKT down-regulates the activation of the mTOR signaling pathway. We also show that inhibition of mTOR with rapamycin, as well as silencing mTOR gene product expression using mTOR-specific small interfering RNA, decreased phosphorylation of mTOR signaling proteins and induced cell cycle arrest and apoptosis in ALK+ ALCL cells. Cell cycle arrest was associated with modulation of G 1-S-phase regulators, including the cyclin-dependent kinase inhibitors p21waf1 and p27kip1. Apoptosis following inhibition of mTOR expression or function was associated with down-regulation of antiapoptotic proteins, including c-FLIP, MCL-1, and BCL-2. These findings suggest that the mTOR pathway contributes to nucleophosmin-ALK/PI3K/AKT-mediated tumorigenesis and that inhibition of mTOR represents a potential therapeutic strategy in ALK+ ALCL.

Original languageEnglish
Pages (from-to)6589-6597
Number of pages9
JournalCancer Research
Volume66
Issue number13
DOIs
StatePublished - Jul 1 2006
Externally publishedYes

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Anaplastic Large-Cell Lymphoma
Sirolimus
Cell Survival
Neoplasms
Phosphatidylinositol 3-Kinase
Phosphorylation
Cell Cycle Checkpoints
anaplastic lymphoma kinase
Down-Regulation
TOR Serine-Threonine Kinases
Ribosomal Protein S6
Eukaryotic Initiation Factor-4E
Apoptosis
70-kDa Ribosomal Protein S6 Kinases
Cyclin-Dependent Kinases
Protein-Serine-Threonine Kinases
Phosphoproteins
Tumor Cell Line
S Phase
Adenoviridae

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Activation of mammalian target of rapamycin signaling pathway contributes to tumor cell survival in anaplastic lymphoma kinase-positive anaplastic large cell lymphoma. / Vega, Francisco; Medeiros, L. Jeffrey; Leventaki, Vasiliki; Atwell, Coralyn; Cho, Jeong Hee; Tian, Ling; Claret, Francois Xavier; Rassidakis, George Z.

In: Cancer Research, Vol. 66, No. 13, 01.07.2006, p. 6589-6597.

Research output: Contribution to journalArticle

Vega, Francisco ; Medeiros, L. Jeffrey ; Leventaki, Vasiliki ; Atwell, Coralyn ; Cho, Jeong Hee ; Tian, Ling ; Claret, Francois Xavier ; Rassidakis, George Z. / Activation of mammalian target of rapamycin signaling pathway contributes to tumor cell survival in anaplastic lymphoma kinase-positive anaplastic large cell lymphoma. In: Cancer Research. 2006 ; Vol. 66, No. 13. pp. 6589-6597.
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abstract = "Anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma (ALCL) frequently carries the t(2;5)(p23;q35) resulting in aberrant expression of chimeric nucleophosmin-ALK. Previously, nucleophosmin-ALK has been shown to activate phosphatidylinositol 3-kinase (PI3K) and its downstream effector, the serine/threonine kinase AKT. In this study, we hypothesized that the mammalian target of rapamycin (mTOR) pathway, which functions downstream of AKT, mediates the oncogenic effects of activated PI3K/AKT in ALK+ ALCL. Here, we provide evidence that mTOR signaling phosphoproteins, including mTOR, eukaryotic initiation factor 4E-binding protein-1, p70S6K, and ribosomal protein S6, are highly phosphorylated in ALK+ ALCL cell lines and tumors. We also show that AKT activation contributes to mTOR phosphorylation, at least in part, as forced expression of constitutively active AKT by myristoylated AKT adenovirus results in increased phosphorylation of mTOR and its downstream effectors. Conversely, inhibition of AKT expression or activity results in decreased mTOR phosphorylation. In addition, pharmacologic inhibition of PI3K/AKT down-regulates the activation of the mTOR signaling pathway. We also show that inhibition of mTOR with rapamycin, as well as silencing mTOR gene product expression using mTOR-specific small interfering RNA, decreased phosphorylation of mTOR signaling proteins and induced cell cycle arrest and apoptosis in ALK+ ALCL cells. Cell cycle arrest was associated with modulation of G 1-S-phase regulators, including the cyclin-dependent kinase inhibitors p21waf1 and p27kip1. Apoptosis following inhibition of mTOR expression or function was associated with down-regulation of antiapoptotic proteins, including c-FLIP, MCL-1, and BCL-2. These findings suggest that the mTOR pathway contributes to nucleophosmin-ALK/PI3K/AKT-mediated tumorigenesis and that inhibition of mTOR represents a potential therapeutic strategy in ALK+ ALCL.",
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AU - Medeiros, L. Jeffrey

AU - Leventaki, Vasiliki

AU - Atwell, Coralyn

AU - Cho, Jeong Hee

AU - Tian, Ling

AU - Claret, Francois Xavier

AU - Rassidakis, George Z.

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