TY - JOUR
T1 - Expression and effects of inhibition of type I insulin-like growth factor receptor tyrosine kinase in mantle cell lymphoma
AU - Vishwamitra, Deeksha
AU - Shi, Ping
AU - Wilson, Desiree
AU - Manshouri, Roxsan
AU - Vega, Francisco
AU - Schlette, Ellen J.
AU - Amin, Hesham M.
PY - 2011/6
Y1 - 2011/6
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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U2 - 10.3324/haematol.2010.031567
DO - 10.3324/haematol.2010.031567
M3 - Article
C2 - 21330319
AN - SCOPUS:79958042289
SN - 0390-6078
VL - 96
SP - 874
EP - 880
JO - Haematologica
JF - Haematologica
IS - 6
ER -