Expression and effects of inhibition of type I insulin-like growth factor receptor tyrosine kinase in mantle cell lymphoma

Deeksha Vishwamitra, Ping Shi, Desiree Wilson, Roxsan Manshouri, Francisco Vega, Ellen J. Schlette, Hesham M. Amin

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

Background Type I insulin-like growth factor receptor (IGF-IR) tyrosine kinase induces significant oncogenic effects. Strategies to block IGF-IR signaling are being tested in clinical trials that include patients with aggressive solid malignancies. Mantle cell lymphoma is a B-cell neoplasm with poor prognosis and a tendency to develop resistance. The expression and potential significance of IGF-IRin mantle cell lymphoma are not known. Design and Methods We used reverse transcriptase polymerase chain reaction, quantitative real-time polymerasecha in reaction, immunoprecipitation, western blotting, flow cytometry, and immunohisto-chemistryto analyze the expression of IGF-IRmRNA, and IGF-IR and pIGF-IR proteins in mantle cell lymphoma cell lines and patients' specimens. Selective and specific blockade of IGF-IR was achieved using picropodophyllin and short-interfering RNA, respectively. Cell viability, apoptosis, cell cycle, cellular morphology, cell proliferation, and target proteins were then analyzed. Results We detected the expression of IGF-IR and pIGF-IR in mantle cell lymphoma cell lines. Notably, IGF-IR molecules/cell were markedly increased in mantle cell lymphoma cell lines compared with human B-lymphocytes. IGF-IR and pIGF-IR were also detected in 78% and 74%, respectively, of 23 primary mantle cell lymphoma specimens. Treatment of serum-deprived mantle cell lymphoma cell lines with IGF-I salvaged these cells from apoptosis. Selective inhibition ofIGF-IR by picropodophyll in decreased the viability and proliferation of mantle cell lymphoma cell lines, and induced apoptosis and cell cycle arrest. Selective inhibition of IGF-IR was associated with caspase-3, caspase-8, caspase-9, and PARP cleavage, cytochrome c release, up-regulation of cyclin B1, and down-regulation of cyclin D1, pCdc2, pIRS-1, pAkt, and pJnk. Similarresults were obtained by using IGF-IR short-interfering RNA. In addition, picropodophyll in decreased the viability and proliferation of primary mantle cell lymphoma cells that expressed IGF-IR. Conclusions IGF-IR is up-regulated and frequently activated in mantle cell lymphoma. Our data suggest that IGF-IR could be a molecular target for the treatment of mantle cell lymphoma.

Original languageEnglish
Pages (from-to)874-880
Number of pages7
JournalHaematologica
Volume96
Issue number6
DOIs
StatePublished - Jun 1 2011
Externally publishedYes

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Mantle-Cell Lymphoma
IGF Type 1 Receptor
Protein-Tyrosine Kinases
Cell Line
Apoptosis
Small Interfering RNA
B-Lymphocytes
Cyclin B1
Caspase 9
Caspase 8
Cyclin D1
Cell Cycle Checkpoints
Cytochromes c
Reverse Transcriptase Polymerase Chain Reaction
Insulin-Like Growth Factor I
Immunoprecipitation
Caspase 3
Neoplasms
Cell Survival
Cell Cycle

Keywords

  • AXL1717
  • IGF-IR
  • Mantle cell lymphoma
  • Picropodophyllin
  • Rituximab

ASJC Scopus subject areas

  • Hematology

Cite this

Expression and effects of inhibition of type I insulin-like growth factor receptor tyrosine kinase in mantle cell lymphoma. / Vishwamitra, Deeksha; Shi, Ping; Wilson, Desiree; Manshouri, Roxsan; Vega, Francisco; Schlette, Ellen J.; Amin, Hesham M.

In: Haematologica, Vol. 96, No. 6, 01.06.2011, p. 874-880.

Research output: Contribution to journalArticle

Vishwamitra, Deeksha ; Shi, Ping ; Wilson, Desiree ; Manshouri, Roxsan ; Vega, Francisco ; Schlette, Ellen J. ; Amin, Hesham M. / Expression and effects of inhibition of type I insulin-like growth factor receptor tyrosine kinase in mantle cell lymphoma. In: Haematologica. 2011 ; Vol. 96, No. 6. pp. 874-880.
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AU - Shi, Ping

AU - Wilson, Desiree

AU - Manshouri, Roxsan

AU - Vega, Francisco

AU - Schlette, Ellen J.

AU - Amin, Hesham M.

PY - 2011/6/1

Y1 - 2011/6/1

N2 - Background Type I insulin-like growth factor receptor (IGF-IR) tyrosine kinase induces significant oncogenic effects. Strategies to block IGF-IR signaling are being tested in clinical trials that include patients with aggressive solid malignancies. Mantle cell lymphoma is a B-cell neoplasm with poor prognosis and a tendency to develop resistance. The expression and potential significance of IGF-IRin mantle cell lymphoma are not known. Design and Methods We used reverse transcriptase polymerase chain reaction, quantitative real-time polymerasecha in reaction, immunoprecipitation, western blotting, flow cytometry, and immunohisto-chemistryto analyze the expression of IGF-IRmRNA, and IGF-IR and pIGF-IR proteins in mantle cell lymphoma cell lines and patients' specimens. Selective and specific blockade of IGF-IR was achieved using picropodophyllin and short-interfering RNA, respectively. Cell viability, apoptosis, cell cycle, cellular morphology, cell proliferation, and target proteins were then analyzed. Results We detected the expression of IGF-IR and pIGF-IR in mantle cell lymphoma cell lines. Notably, IGF-IR molecules/cell were markedly increased in mantle cell lymphoma cell lines compared with human B-lymphocytes. IGF-IR and pIGF-IR were also detected in 78% and 74%, respectively, of 23 primary mantle cell lymphoma specimens. Treatment of serum-deprived mantle cell lymphoma cell lines with IGF-I salvaged these cells from apoptosis. Selective inhibition ofIGF-IR by picropodophyll in decreased the viability and proliferation of mantle cell lymphoma cell lines, and induced apoptosis and cell cycle arrest. Selective inhibition of IGF-IR was associated with caspase-3, caspase-8, caspase-9, and PARP cleavage, cytochrome c release, up-regulation of cyclin B1, and down-regulation of cyclin D1, pCdc2, pIRS-1, pAkt, and pJnk. Similarresults were obtained by using IGF-IR short-interfering RNA. In addition, picropodophyll in decreased the viability and proliferation of primary mantle cell lymphoma cells that expressed IGF-IR. Conclusions IGF-IR is up-regulated and frequently activated in mantle cell lymphoma. Our data suggest that IGF-IR could be a molecular target for the treatment of mantle cell lymphoma.

AB - Background Type I insulin-like growth factor receptor (IGF-IR) tyrosine kinase induces significant oncogenic effects. Strategies to block IGF-IR signaling are being tested in clinical trials that include patients with aggressive solid malignancies. Mantle cell lymphoma is a B-cell neoplasm with poor prognosis and a tendency to develop resistance. The expression and potential significance of IGF-IRin mantle cell lymphoma are not known. Design and Methods We used reverse transcriptase polymerase chain reaction, quantitative real-time polymerasecha in reaction, immunoprecipitation, western blotting, flow cytometry, and immunohisto-chemistryto analyze the expression of IGF-IRmRNA, and IGF-IR and pIGF-IR proteins in mantle cell lymphoma cell lines and patients' specimens. Selective and specific blockade of IGF-IR was achieved using picropodophyllin and short-interfering RNA, respectively. Cell viability, apoptosis, cell cycle, cellular morphology, cell proliferation, and target proteins were then analyzed. Results We detected the expression of IGF-IR and pIGF-IR in mantle cell lymphoma cell lines. Notably, IGF-IR molecules/cell were markedly increased in mantle cell lymphoma cell lines compared with human B-lymphocytes. IGF-IR and pIGF-IR were also detected in 78% and 74%, respectively, of 23 primary mantle cell lymphoma specimens. Treatment of serum-deprived mantle cell lymphoma cell lines with IGF-I salvaged these cells from apoptosis. Selective inhibition ofIGF-IR by picropodophyll in decreased the viability and proliferation of mantle cell lymphoma cell lines, and induced apoptosis and cell cycle arrest. Selective inhibition of IGF-IR was associated with caspase-3, caspase-8, caspase-9, and PARP cleavage, cytochrome c release, up-regulation of cyclin B1, and down-regulation of cyclin D1, pCdc2, pIRS-1, pAkt, and pJnk. Similarresults were obtained by using IGF-IR short-interfering RNA. In addition, picropodophyll in decreased the viability and proliferation of primary mantle cell lymphoma cells that expressed IGF-IR. Conclusions IGF-IR is up-regulated and frequently activated in mantle cell lymphoma. Our data suggest that IGF-IR could be a molecular target for the treatment of mantle cell lymphoma.

KW - AXL1717

KW - IGF-IR

KW - Mantle cell lymphoma

KW - Picropodophyllin

KW - Rituximab

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