Targeting for insulin-like growth factor-I receptor with short hairpin RNA for human digestive/gastrointestinal cancers

Wang, Yu; Adachi, Yasushi; Imsumran, Arisa; Yamamoto, Hiroyuki; Piao, Wenhua; Li, Hua; Masanori,; Arimura, Yoshiaki; Park, Mi Young; Kim, Dalrae; Lee, Choon Taek; Carbone, David P.; Imai, Kohzoh; Shinomura, Yasuhisa

doi:10.1007/s00535-009-0151-6

Cited by 21 publications

(13 citation statements)

References 40 publications

(59 reference statements)

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“…Loss of IGF1R expression did not inhibit the growth in full medium of FGFR2 -amplified SNU-16 but it is possible that the active IGF pathway might acquire ascendancy after abrogation of FGFR pathway activity. Our findings that IGF-1 stimulates phosphorylation of the type I IGF receptor and Akt in MET -amplified SNU-5 are consistent with reports that IGF-1 increases trypan blue uptake and protects against cell death induced with 5% ethanol [16] in MET -amplified MKN45 [36], and that an shRNA against the type I IGF receptor increased MKN45 cell death and decreased colony formation in soft agar [17]. The IGF signal transduction pathway may be more important than appreciated in cells with amplified HER2, FGFR2 or MET and consideration should be given to dual targeting with an IGF inhibitor to limit onset of resistance.…”

Section: Discussionsupporting

confidence: 92%

“…Growth inhibition was observed also after knockdown of the type I IGF receptor in gastric cancer cells isolated from patients. Previously, reduced colony formation has been shown after inhibition of the type I IGF receptor with shRNA and the αIR3 antibody in MET -amplified MKN45 and in tumour explants, respectively [17, 40]. Our data provide the first demonstration of the importance of the type I IGF receptor in the proliferation of triple-negative gastric cancer cells.…”

Section: Discussionsupporting

confidence: 69%

“…A second study reported IGF1R amplification especially in CIN and GS subtypes [15]. Insulin-like growth factor (IGF) pathway activity has been reported in MET -amplified gastric cancer cells [16, 17] and the pathway has been proposed as a means by which HER2 -amplified NCI-N87 circumvent lapatinib inhibition [18]. The IGF-dependence of triple-negative gastric cancer cells has not been investigated.…”

Section: Introductionmentioning

confidence: 99%

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Importance of the type I insulin-like growth factor receptor inHER2, FGFR2andMET-unamplified gastric cancer with and without Ras pathway activation

2016

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Amplification of seven oncogenes: HER2, EGFR, FGFR1, FGFR2, MET, KRAS and IGF1R has been identified in gastric cancer. The first five are targeted therapeutically in patients with HER2-positivity, FGFR2- or MET-amplification but the majority of patients are triple-negative and require alternative strategies. Our aim was to evaluate the importance of the IGF1R tyrosine kinase in triple-negative gastric cancer with and without oncogenic KRAS, BRAF or PI3K3CA mutations. Cell lines and metastatic tumor cells isolated from patients expressed IGF1R, and insulin-like growth factor-1 (IGF-1) activated the PI3-kinase/Akt and Ras/Raf/MAP-kinase pathways. IGF-1 protected triple-negative cells from caspase-dependent apoptosis and anoikis. Protection was mediated via the PI3-kinase/Akt pathway. Remarkably, IGF-1-dependent cell survival was greater in patient samples. IGF-1 stimulated triple-negative gastric cancer cell growth was prevented by IGF1R knockdown and Ras/Raf/MAP-kinase pathway inhibition. The importance of the receptor in cell line and metastatic tumor cell growth in serum-containing medium was demonstrated by knockdown and pharmacological inhibition with figitumumab. The proportions of cells in S-phase and mitotic-phase, and Ras/Raf/MAP-kinase pathway activity, were reduced concomitantly. KRAS-addicted and BRAF-impaired gastric cancer cells were particularly susceptible. In conclusion, IGF1R and the IGF signal transduction pathway merit consideration as potential therapeutic targets in patients with triple-negative gastric cancer.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 69%

Section: Introductionmentioning

confidence: 99%

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Importance of the type I insulin-like growth factor receptor inHER2, FGFR2andMET-unamplified gastric cancer with and without Ras pathway activation

2016

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“…The array data were analyzed using R environment and Bioconductor packages, similar to our published studies. 21,23 The ‘Lumi’ package 24,25 was used to preprocess the data using variance stabilization transformation (variance within array), 26,27 quantile normalization (variance between arrays) and background subtraction. 24,25 Quality measures were taken before and after preprocessing using the arrayQualityMetrics package 28,29 to remove outliers determined by at least two out of the three tests in the package, and care was taken that the normalization did not skew the data (two TH samples out of the 42 failed to pass the cutoff and were therefore removed from the analysis).…”

Section: Methodsmentioning

confidence: 99%

The synaptoneurosome transcriptome: a model for profiling the emolecular effects of alcohol

et al. 2014

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Chronic alcohol consumption changes gene expression, likely causing persistent remodeling of synaptic structures via altered translation of mRNAs within synaptic compartments of the cell. We profiled the transcriptome from synaptoneurosomes (SNs) and paired total homogenates (THs) from mouse amygdala following chronic voluntary alcohol consumption. In SN, both the number of alcohol-responsive mRNAs and the magnitude of fold-change were greater than in THs, including many GABA-related mRNAs upregulated in SNs. Furthermore, SN gene co-expression analysis revealed a highly connected network, demonstrating coordinated patterns of gene expression and highlighting alcohol-responsive biological pathways, such as long-term potentiation, long-term depression, glutamate signaling, RNA processing and upregulation of alcohol-responsive genes within neuroimmune modules. Alterations in these pathways have also been observed in the amygdala of human alcoholics. SNs offer an ideal model for detecting intricate networks of coordinated synaptic gene expression and may provide a unique system for investigating therapeutic targets for the treatment of alcoholism.

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“…Inhibition of IGF-1R signaling pathway by shRNA, among other ways has been implicated to have antitumor activities in ESCC183637. IGF-1R monoclonal antibodies displayed in vitro and in vivo antitumor effects in various cancers.…”

Section: Discussionmentioning

confidence: 99%

Antitumor effects and molecular mechanisms of figitumumab, a humanized monoclonal antibody to IGF-1 receptor, in esophageal carcinoma

Zhang

Shen

Wang

et al. 2014

Sci Rep

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The insulin-like growth factor type 1 receptor (IGF-1R) plays an essential role in the development of numerous cancers. Figitumumab (CP) is not only a monocloncal antibody, it also has agonist activity on IGF-1R. The antitumor activity of CP in esophageal squamous cell carcinoma (ESCC) is still unclear. In our study, we identified IGF-1R as an independent prognostic factor in ESCC patients, and investigated the antitumor effects of CP in ESCC cell lines. CP suppressed tumor growth and sensitized cells to chemotherapeutic drugs. In addition, CP inhibited cell proliferation, migration, colony forming activity and anti-apoptosis induced by IGF-1. Our results showed that CP not only inhibited IGF-1 induced receptor autophosphorylation and downstream signaling, but also triggered β-arrestin1 and G protein-coupled receptor kinases (GRKs) mediated ERK1/2 activation, indicating CP as a biased agonist for IGF-1R. Inhibition of ERK1/2 enhanced the antitumor activity of CP. Furthermore, CP was a more powerful agonist for IGF-1R down-regulation than IGF-1, and dysregulation of β-arrestin1 and GRKs affected this down-regulation. Thus, we demonstrated antitumor activities of CP on ESCC, and as a biased agonist, CP induced ERK1/2 activation and receptor down-regulation required β-arrestin1 and GRKs, suggesting a promising role for targeting IGF-1R in ESCC.

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Targeting for insulin-like growth factor-I receptor with short hairpin RNA for human digestive/gastrointestinal cancers

Abstract: shIGF-IR may have therapeutic utility in human digestive/gastrointestinal cancers, both alone and in combination with chemotherapy.

Cited by 21 publications

References 40 publications

Importance of the type I insulin-like growth factor receptor inHER2, FGFR2andMET-unamplified gastric cancer with and without Ras pathway activation

Importance of the type I insulin-like growth factor receptor inHER2, FGFR2andMET-unamplified gastric cancer with and without Ras pathway activation

The synaptoneurosome transcriptome: a model for profiling the emolecular effects of alcohol

Antitumor effects and molecular mechanisms of figitumumab, a humanized monoclonal antibody to IGF-1 receptor, in esophageal carcinoma

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