Type 1 Insulin-like Growth Factor Receptor Translocates to the Nucleus of Human Tumor Cells

Aleksic, Tamara; Chitnis, Meenali M.; Perestenko, Olga V.; Gao, Shan; Thomas, Peter H.; Turner, Gareth D. H.; Protheroe, Andrew; Howarth, Mark; Macaulay, Valentine M.

doi:10.1158/0008-5472.can-10-0052

Cited by 183 publications

(245 citation statements)

References 22 publications

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“…An initial report of intact IGF-1 receptors present in the nucleus (Chen and Roy 1996) has been confirmed and extended in recent reports from two groups (Aleksic et al 2010;Deng et al 2010;Sehat et al 2010). Both groups indicate that this relocalization from plasma membrane to nucleus is IGF-1 dependent and that the nuclear receptor may function as a transcriptional coactivator.…”

Section: Igf-1mentioning

confidence: 65%

Receptor Tyrosine Kinases in the Nucleus

Carpenter

Liao

2013

Cold Spring Harbor Perspectives in Biology

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To date, 18 distinct receptor tyrosine kinases (RTKs) are reported to be trafficked from the cell surface to the nucleus in response to ligand binding or heterologous agonist exposure. In most cases, an intracellular domain (ICD) fragment of the receptor is generated at the cell surface and translocated to the nucleus, whereas for a few others the intact receptor is translocated to the nucleus. ICD fragments are generated by several mechanisms, including proteolysis, internal translation initiation, and messenger RNA (mRNA) splicing. The most prevalent mechanism is intramembrane cleavage by g-secretase. In some cases, more than one mechanism has been reported for the nuclear localization of a specific RTK. The generation and use of RTK ICD fragments to directly communicate with the nucleus and influence gene expression parallels the production of ICD fragments by a number of non-RTK cell-surface molecules that also influence cell proliferation. This review will be focused on the individual RTKs and to a lesser extent on other growth-related cell-surface transmembrane proteins.

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Section: Igf-1mentioning

confidence: 65%

Receptor Tyrosine Kinases in the Nucleus

Carpenter

Liao

2013

Cold Spring Harbor Perspectives in Biology

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“…47,48 It seems possible that differential receptor downstream signals and nuclear translocation of the IGF1R have a higher impact on IGF1R signaling in cancer cells than receptor expression levels alone.…”

Section: Massoner Et Almentioning

confidence: 99%

Expression of the IGF Axis Is Decreased in Local Prostate Cancer but Enhanced after Benign Prostate Epithelial Differentiation and TGF-β Treatment

Massoner¹,

Rennau²,

Heidegger³

et al. 2011

The American Journal of Pathology

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The insulin-like growth factor (IGF) axis is a molecular pathway intensively investigated in cancer research. Clinical trials targeting the IGF1 receptor (IGF1R) in different tumors, including prostate cancer, are under way. Although studies on the IGF axis in prostate cancer have already entered into clinical trials, the expression and functional role of the IGF axis in benign prostate and in prostate cancer needs to be better defined. We determined mRNA expression levels of the IGF axis in microdissected tissue specimens of local prostate cancer using quantitative PCR. All members of the IGF axis, including IGF1, IGF2, IGF binding proteins 1 through 6, and insulin receptor, were measured in both the stromal and epithelial compartments of the prostate. IGF1, IGF2, IGF1R, and insulin receptor were down-regulated in local prostate cancer tissue compared with matched benign tissue, suggesting that the IGF axis is not induced during prostate cancer development. Using a new prostate epithelial differentiation model, we demonstrate that the expression of the IGF axis is enhanced during normal prostate epithelial differentiation and regulated by tumor growth factor (TGF)-␤. Our data reveal a functional role of the IGF axis in prostate differentiation, underscoring the importance of the IGF axis in normal development and emphasizing the importance of accurate target validation before moving to advanced clinical trials.

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“…Overexpression of IGF1R is frequently observed in tumor cell lines and human cancers including non-small cell lung cancer (NSCLC) and mediates both tumor growth and resistance to EGF receptor (EGFR/ ERBB) inhibitors (6). Compelling new data have shown that both the a and b subunits of IGF1R can translocate to the nucleus and directly regulate transcription (7). Nuclear IGF1R has been detected in tumor cell lines and tumor biopsies, and early data suggest an association with poor prognosis (7).…”

Section: Introductionmentioning

confidence: 99%

“…Compelling new data have shown that both the a and b subunits of IGF1R can translocate to the nucleus and directly regulate transcription (7). Nuclear IGF1R has been detected in tumor cell lines and tumor biopsies, and early data suggest an association with poor prognosis (7). IGF1R has also been implicated in the ability of drug-resistant cancer cells to maintain viability (8).…”

Section: Introductionmentioning

confidence: 99%

Molecular Predictors of Sensitivity to the Insulin-like Growth Factor 1 Receptor Inhibitor Figitumumab (CP-751,871)

Pavlı́ček

Lira

Lee

et al. 2013

Molecular Cancer Therapeutics

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Figitumumab (CP-751,871), a potent and fully human monoclonal anti-insulin-like growth factor 1 receptor (IGF1R) antibody, has been investigated in clinical trials of several solid tumors. To identify biomarkers of sensitivity and resistance to figitumumab, its in vitro antiproliferative activity was analyzed in a panel of 93 cancer cell lines by combining in vitro screens with extensive molecular profiling of genomic aberrations. Overall response was bimodal and the majority of cell lines were resistant to figitumumab. Nine of 15 sensitive cell lines were derived from colon cancers. Correlations between genomic characteristics of cancer cell lines with figitumumab antiproliferative activity revealed that components of the IGF pathway, including IRS2 (insulin receptor substrate 2) and IGFBP5 (IGF-binding protein 5), played a pivotal role in determining the sensitivity of tumors to single-agent figitumumab. Tissue-specific differences among the top predictive genes highlight the need for tumor-specific patient selection strategies. For the first time, we report that alteration or expression of the MYB oncogene is associated with sensitivity to IGF1R inhibitors. MYB is dysregulated in hematologic and epithelial tumors, and IGF1R inhibition may represent a novel therapeutic opportunity. Although growth inhibitory activity with single-agent figitumumab was relatively rare, nine combinations comprising figitumumab plus chemotherapeutic agents or other targeted agents exhibited properties of synergy. Inhibitors of the ERBB family were frequently synergistic and potential biomarkers of drug synergy were identified. Several biomarkers of antiproliferative activity of figitumumab both alone and in combination with other therapies may inform the design of clinical trials evaluating IGF1R inhibitors.

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Type 1 Insulin-like Growth Factor Receptor Translocates to the Nucleus of Human Tumor Cells

Cited by 183 publications

References 22 publications

Receptor Tyrosine Kinases in the Nucleus

Receptor Tyrosine Kinases in the Nucleus

Expression of the IGF Axis Is Decreased in Local Prostate Cancer but Enhanced after Benign Prostate Epithelial Differentiation and TGF-β Treatment

Molecular Predictors of Sensitivity to the Insulin-like Growth Factor 1 Receptor Inhibitor Figitumumab (CP-751,871)

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