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Knockdown IGF-1R triggers viral RNA sensors MDA5- and RIG-1-mediated the mitochondrial apoptosis in colonic cancer cells

ABSTRACT: The important role of IGF-1R in cancers has been well established. Classical model involves IGF-1/2 binding to IGF-1R, following activation of the PI3K/Akt pathway, thereby promoting cell proliferation, apoptosis inhibition and treatment resistance. While IGF-1R has become a promising target for cancer therapy, clinical disclosures subsequently have been less encouraging. The question is whether targeting IGF/IGF-1R still holds therapeutic potential. Here we show a novel mechanism that knockdown IGF-1R surprisingly triggers cytoplasmic viral RNA sensors MDA5 and RIG-1, leading to mitochondrial apoptosis in cancer. We analyzed MDA5 and RIG-1 in the intestinal epithelium of IGF-1R knockdown mice. Igf1r+/- mice demonstrated higher MDA5 and RIG-1 than WT mice. IGF-1R knockdown-triggered MDA5 and RIG-1 was further analyzed in human cancer and normal cells. Increased MDA5 and RIG-1 were clearly seen in the cytoplasm identified by immunofluoresce in the cells silenced IGF-1R. Block off IGF-1R downstream PI3K/Akt did not impact on MDA5 and RIG-1 expression. IGF-1R knockdown-triggered MDA5 and RIG-1 and their signaling pathways were similar to those of viral RNA mimetic poly(I:C) had. IGF-1R knockdown-triggered MDA5 and RIG-1 led to cancer apoptosis through activation of the mitochondrial pathway. In vivo assay, Igf1r+/- mice strongly resisted AOM-induced colonic tumorigenesis through triggering MDA¬5- and RIG-1-mediated apoptosis. Notably, RIG-I and MDA5-mediated proapoptotic signaling pathway is preferential active in cancer cells. These data suggest that targeting IGF-1R-triggered MDA5 and RIG-1 might have therapeutic potential for cancer treatment.

ORGANISM(S): Homo sapiens

PROVIDER: GSE122534 | GEO | 2019/11/30

REPOSITORIES: GEO

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Knockdown IGF-1R triggers viral RNA sensors MDA5- and RIG-1-mediated the mitochondrial apoptosis in colonic cancer cells

Project description:Knockdown IGF-1R triggers viral RNA sensors MDA5- and RIG-1-mediated the mitochondrial apoptosis in colonic cancer cells

| PRJNA505500 | ENA

Genome-wide analysis of insulin-like growth factor 1 receptor (IGF1R) binding sites in DFB cells

Project description:The insulin-like growth factor 1 receptor (IGF-1R) plays crucial roles in developmental and cancer biology. Most of its biological effects have been ascribed to its tyrosine kinase activity. We report that IGF-1 promotes the modification of IGF-1R by small ubiquitin-like modifier protein-1 (SUMO-1) and its translocation to the nucleus. Nuclear IGF-1R associated with enhancer-like elements and increased transcription in reporter assays. We used ChIP-seq to examine the interaction of IGF-1R with DNA on a genome-wide scale. Analysis of the data set resulted in 568 candidate peaks, that is, statistically significant IGF-1R-enriched regions. The IGF-1R-enriched regions were divided into five classes on the basis of their location relative to known genes. Most of the IGF-1R-interacting sites (80%) were located distal from any annotated gene (intergenic), 6.3% were located in introns, 6.3% in exons, 3.4% were <20 kb upstream of an annotated transcript start site (5'UTR + 20 kb upstream), and 3.6% were <20 kb downstream of an annotated transcript end site (3'UTR + 20 kb downstream). Analysis of the genomic interaction of IGF1R in DFB cells

2010-08-25 | E-GEOD-23792 | biostudies-arrayexpress

Microenvironment-driven IGF-1R/PI3K signaling underlies acquired resistance to CSF1R inhibition in gliomas (CGH)

Project description:Macrophages accumulate with glioblastoma multiforme (GBM) progression, and can be acutely targeted via inhibition of colony stimulating factor-1 receptor (CSF-1R) to regress high-grade tumors in animal models. However, whether and how resistance emerges in response to sustained CSF-1R blockade is unknown. Here, we investigate whether long-term CSF-1R inhibition can stably regress GBM in preclinical trials. We show that while overall survival is significantly prolonged, tumors recur eventually in >50% of mice. Upon isolation and transplantation of recurrent tumor cells into naïve animals, gliomas re-establish sensitivity to CSF-1R inhibition, indicating that resistance is microenvironment-driven. PI3K pathway activity was elevated in recurrent GBM, driven by macrophage-derived IGF-1 and tumor cell IGF-1R. Consequently, combining IGF-1R or PI3K blockade with continuous CSF-1R inhibition in recurrent tumors significantly prolonged overall survival. By contrast, monotherapy with IGF-1R or PI3K inhibitors in rebound or treatment-naïve tumors was less effective, indicating the necessity of combination therapy to expose PI3K signaling-dependency in recurrent disease. Our findings thus reveal a potential therapeutic approach for treating resistance to CSF-1R inhibitors in the clinical setting.

2016-05-20 | GSE80399 | GEO

Ganitumab and Metformin plus Standard Neoadjuvant Therapy in Stage 2/3 Breast Cancer: Results from the I-SPY2 Adaptively Randomized Platform Trial

Project description:Ganitumab and Metformin was one of the experimental regiments evaluated in I-SPY 2, a neoadjuvant platform trial for high risk, early stage breast cancer. Based on the hypotheses that pre-treatment IGF-1R axis signaling at the expression level may predict response to Ganitumab and Metformin, in pre-defined analyses we assessed 11 genes involved in IGF1R pathway signaling, the IGFBP5/IGFBP4 ratio, and two IGFR expression signatures to test their association with pCR (complete pathologic response).

2021-08-24 | GSE180962 | GEO

Genome-wide analysis of insulin-like growth factor 1 receptor (IGF1R) binding sites in DFB cells

2010-08-25 | GSE23792 | GEO

Insulin receptor substrate adaptor proteins mediate prognostic gene expression profiles in breast cancer

Project description:Therapies targeting the type I insulin-like growth factor receptor (IGF-1R) have not been developed with predictive biomarkers to identify tumors with receptor activation. We have previously shown that the insulin receptor substrate (IRS) adaptor proteins are necessary for linking IGF1R to downstream signaling pathways and the malignant phenotype in breast cancer cells. The purpose of this study was to identify gene expression profiles downstream of IGF1R and its two adaptor proteins. IRS-null breast cancer cells (T47D-YA) were engineered to express IRS-1 or IRS-2 alone and their ability to mediate IGF ligand-induced proliferation, motility, and gene expression determined. Global gene expression signatures reflecting IRS adaptor specific and primary vs. secondary ligand response were derived (Early IRS-1, Late IRS-1, Early IRS-2 and Late IRS-2) and functional pathway analysis examined. IRS isoforms mediated distinct gene expression profiles, functional pathways, and breast cancer subtype association. For example, IRS-1/2-induced TGFb2 expression and blockade of TGFb2 abrogated IGF-induced cell migration. In addition, the prognostic value of IRS proteins was significant in the luminal B breast tumor subtype. Univariate and multivariate analyses confirmed that IRS adaptor signatures correlated with poor outcome as measured by recurrence-free and overall survival. Thus, IRS adaptor protein expression is required for IGF ligand responses in breast cancer cells. IRS-specific gene signatures represent accurate surrogates of IGF activity and could predict response to anti-IGF therapy in breast cancer.

2016-03-05 | GSE78916 | GEO

LGP2 binds PACT to regulate RIG-I- and MDA5-mediated antiviral response

Project description:The RIG-I-like receptors (RLRs: RIG-I, MDA5 and LGP2) trigger inflammatory and antiviral responses by sensing non-self RNA molecules produced during viral replication. LGP2 regulation of RIG-I and MDA5-dependant type-I interferon signaling is a matter of controversy. Here we show that LGP2 interacts with different components of the RNA silencing machinery. Particularly, we identified a direct protein-protein interaction between LGP2 and interferon-inducible double-stranded RNA-dependent protein kinase activator A (PACT). The LGP2-PACT interaction is mediated by the regulatory C-terminal domain of LGP2 and is necessary for inhibiting the RIG-I- and amplifying the MDA5-responses. We describe a point mutation within LGP2 that disrupts LGP2-PACT interaction and leads to the loss of LGP2 regulatory activity over RIG-I and MDA5. These results provide a model in which PACT-LGP2 interaction regulates RIG-I and MDA5 inflammatory response and allows cellular RNA silencing machinery to coordinate the innate immune response.

2019-10-02 | PXD013191 | Pride

Identification of phosphorylation sites in the IGF-1 Receptor

Project description:Although Insulin-like Growth Factor (IGF-1) signaling promotes tumor growth and cancer progression, IGF-1 Receptor-targeted therapies have shown poor clinical efficacy. The mechanistic basis for this is unclear as is our understanding of what distinguishes IGF-1R signaling from the closely related Insulin receptor (IR) signaling. This study illuminates both issues. A site in the IGF-1R C-terminal tail incorporating two tyrosines that are not present in the Insulin receptor (IR) was previously shown to be essential for IGF-1-mediated cancer cell survival, migration and tumorigenic growth. Here, we establish that the Y1250/Y1251 site is autophosphorylated in a cell adhesion-dependent manner.

2020-05-15 | PXD017644 | Pride

A paracrine IGF1/IGF1R-PI3K signaling loop underlies resistance to CSF-1R inhibition in GBM

Project description:Glioblastoma multiforme (GBM) is the most aggressive form of glioma, and is notorious for its terminal prognosis and lack of responsiveness to current treatment approaches. The brain tumor microenvironment (TME) represents a largely untapped reservoir of therapeutic target options in GBM. Here we have focused on the interplay between glioma cells and tumor-associated macrophages/ microglia (TAMs). TAMs accumulate in the gliomas with disease progression, and depend on colony stimulating factor 1 receptor (CSF-1R) signaling for survival. In a recent study from our laboratory, mice bearing high-grade gliomas were treated with a CSF-1R inhibitor, BLZ945 (Novartis), and tumors regressed significantly after just 7 days of treatment (PMID: 24056773). Here we investigate whether long-term treatment of high-grade gliomas with BLZ945 would result in stable management of disease in a mouse model of proneural GBM. We show that ~44% of mice survived to the trial end point (EP) with minimal disease by MRI and histology, whereas ~56% of mice showed tumor recurrence (Reb). Serial transplantation of rebound tumor cells into naïve animals re-established BLZ945 responsiveness, suggesting a role for the microenvironment in supporting recurrent disease. Indeed, RNA-seq analysis on FACS purified tumor cells and TAMs from EP and Reb tumors showed elevated PI3K signaling in Reb tumors, driven by a heterotypic paracrine interaction between TAM-derived IGF-1 and tumor cell IGF-1R. We performed combination trials to block IGF-1R or downstream PI3K signaling in rebound tumors with BLZ945 treatment, and were able to significantly prolong overall survival. Given that CSF-1R inhibitors are currently in clinical trials for multiple cancer types including for GBM, understanding the molecular mechanisms that underlie non-responsive/ resistant tumors is timely and critical.

2016-05-20 | GSE69104 | GEO

Transcription profiling of mouse CD8-IGF1R 3T3 cells and 3T3 Vector control treated for 24 h with vehicle or IGF1R inhibitor A-928605 reveals reversal of oncogene transformation and suppression of tumor growth by the novel IGF1R kinase inhibitor A-928605.

Project description:The insulin-like growth factor (IGF) axis is an important signaling pathway in the growth and survival of many cell types and has been implicated in multiple aspects of cancer progression from tumorigenesis to metastasis. The multiple roles of IGF signaling in cancer suggest that selective inhibition of the pathway might yield clinically effective therapeutics. Here we describe A-928605, a novel small molecule inhibitor of the receptor tyrosine kinase responsible for IGF signal transduction. This small molecule is able to abrogate activation of the pathway as shown by effects on the target and downstream effectors and is shown to be effective at inhibiting the proliferation of an oncogene addicted tumor model cell line (CD8-IGF1R 3T3) both in vitro and in vivo. Experiment Overall Design: CD8-IGF1R 3T3 cells and 3T3 Vector control treated for 24 h with vehicle or IGF1R inhibitor A-928605, all with 3 replicates.

2009-06-11 | E-GEOD-14024 | biostudies-arrayexpress

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