Aberrant expression and activation of insulin-like growth factor-1 receptor (IGF-1R) are mediated by an induction of IGF-1R promoter activity and stabilization of IGF-1R mRNA and contributes to growth factor independence and increased survival of the pancreatic cancer cell line MIA PaCa-2

Nair, Prakash; Armond, Daniel T De; Adamo, Martin L.; Strodel, William E.; Freeman, James W.

doi:10.1038/sj.onc.1205044

Cited by 69 publications

(68 citation statements)

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“…Our studies and others have shown that immortal cells can acquire growth factor independence through acquisition of autocrine growth factors (Li et al, 1992;Shirakata et al, 2000;Berquin et al, 2001) or growth factor receptor overexpression (Woods Ignatoski et al, 1999;Worthylake et al, 1999;Nair et al, 2001). In the present study, we found that YB-1 lead to overexpression and activation of EGFR and to EGF-independent proliferation in HMECs.…”

Section: Discussionsupporting

confidence: 61%

Y-box-binding protein 1 confers EGF independence to human mammary epithelial cells

et al. 2005

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The epidermal growth factor receptor (EGFR) is linked to poor outcome in breast cancer, and resistance to hormonal therapy is often accompanied by activation of growth factor receptors. To investigate the mechanism(s) by which EGFR becomes activated in breast cancer, we screened a cDNA expression library for genes that mediate EGF-independent proliferation of human mammary epithelial cells (HMECs). We isolated the NSEP1 cDNA encoding Y-box-binding protein 1 (YB-1), a multifunctional transcriptional and translational regulator. This cDNA conferred growth factor independence to HMECs. YB-1-transduced cells overexpressed EGFR, but ErbB-2 (Her-2/neu) levels were unchanged. Moreover, EGFR was constitutively phosphorylated in the absence of exogenous ligand. In these cells, an EGFR-blocking antibody failed to inhibit proliferation, conditioned medium activity could not be detected, and the synthesis of EGFR ligands was reduced compared to parental cells. This suggests that EGFR is activated in a ligandindependent fashion. However, cell growth could be blocked with an ErbB kinase inhibitor, indicating that EGFR signaling plays a major role in YB-1-induced growth factor independence. Taken together, our results demonstrate that YB-1 overexpression can induce EGF independence in HMECs via activation of the EGFR pathway. This could represent one of the mechanisms by which YB-1 contributes to breast tumor aggressiveness.

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Section: Discussionsupporting

confidence: 61%

Y-box-binding protein 1 confers EGF independence to human mammary epithelial cells

et al. 2005

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“…Previous studies have proposed both IGF-I-dependent mechanisms through ligand-receptor interaction as well as IGF-I-independent mechanisms through a constitutively active receptor to initiate the IGF-IR-dependent signaling cascade. 39 We, therefore, wanted to determine whether autocrine secretion of IGF-I was involved in the activation of IGF-IR in MCL cells. There was no apparent expression of IGF-I by JeKo-1 and Mino cells and probable negligible expression by SP-53 cells.…”

Section: Discussionmentioning

confidence: 99%

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

Vishwamitra¹,

Shi²,

Wilson³

et al. 2011

Haematologica

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The online version of this article has a Supplementary Appendix. BackgroundType 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-IR in mantle cell lymphoma are not known. Design and MethodsWe used reverse transcriptase polymerase chain reaction, quantitative real-time polymerase chain reaction, immunoprecipitation, western blotting, flow cytometry, and immunohistochemistry to analyze the expression of IGF-IR mRNA, 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. ResultsWe 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 of IGF-IR by picropodophyllin 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. Similar results were obtained by using IGF-IR short-interfering RNA. In addition, picropodophyllin decreased the viability and proliferation of primary mantle cell lymphoma cells that expressed IGF-IR. ConclusionsIGF-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. Haematologica 2011;96(6):871-880. doi:10.3324/haematol.2010 Expression and effects of inhibition of type I insulin-like growth factor receptor tyrosine kinase in mantle cell lymphoma

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“…This experiment was performed by treating the cells with the RNA polymerase inhibitor Actinomycin D (AD) (10 mM) for 6 or 9 h before analysis of IGF-1R mRNA levels. Because de novo transcription is completely blocked during these periods, the detected amounts of IGF-1R transcripts will be due to the rate of mRNA degradation (Nair et al, 2001). Cells at resistance levels of 0.04 and 0.1 mM were used in these experiments.…”

Section: Analysis Of Igf-1r Expression and Activitymentioning

confidence: 99%

The insulin-like growth factor-1 receptor inhibitor PPP produces only very limited resistance in tumor cells exposed to long-term selection

et al. 2006

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Aberrant expression and activation of insulin-like growth factor-1 receptor (IGF-1R) are mediated by an induction of IGF-1R promoter activity and stabilization of IGF-1R mRNA and contributes to growth factor independence and increased survival of the pancreatic cancer cell line MIA PaCa-2

Cited by 69 publications

References 51 publications

Y-box-binding protein 1 confers EGF independence to human mammary epithelial cells

Y-box-binding protein 1 confers EGF independence to human mammary epithelial cells

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

The insulin-like growth factor-1 receptor inhibitor PPP produces only very limited resistance in tumor cells exposed to long-term selection

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