The Receptor for Egf and Its Ligands - Expression, Prognostic Value and Target for Therapy in Cancer (Review)

Modjtahedi, Helmout; Dean, Christopher

doi:10.3892/ijo.4.2.277

Cited by 78 publications

(98 citation statements)

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“…The epidermal growth factor (EGF) receptor (EGFR) and its closest family member p185 neu , the product of the HER2 gene, are transmembrane receptor tyrosine kinases (TK), which transduce signals associated with tumor cell proliferation (1)(2)(3)(4). The variety of approaches currently used to target EGFR includes small monoclonal antibody strategy to block ligand binding and TK inhibitors (5)(6)(7).…”

Section: Introductionmentioning

confidence: 99%

Subcellular Distribution of a Fluorescence-Labeled Combi-Molecule Designed to Block Epidermal Growth Factor Receptor Tyrosine Kinase and Damage DNA with a Green Fluorescent Species

Todorova

Larroque

Dauphin-Pierre

et al. 2010

Molecular Cancer Therapeutics

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To monitor the subcellular distribution of mixed epidermal growth factor (EGF) receptor (EGFR)-DNA targeting drugs termed combi-molecules, we designed AL237, a fluorescent prototype, to degrade into a green fluorescent DNA damaging species and FD105, a blue fluorescent EGFR inhibitor. Here we showed that AL237 damaged DNA in the 12.5 to 50 μmol/L range. Despite its size, it blocked EGFR phosphorylation in an enzyme assay (IC 50 = 0.27 μmol/L) and in MDA-MB468 breast cancer cells in the same concentration range as for DNA damage. This translated into inhibition of extracellular signal-regulated kinase 1/2 or BAD phosphorylation and downregulation of DNA repair proteins (XRCC1, ERCC1). Having shown that AL237 was a balanced EGFR-DNA targeting molecule, it was used as an imaging probe to show that (a) green and blue colors were primarily colocalized in the perinuclear and partially in the nucleus in EGFR-or ErbB2-expressing cells, (b) the blue fluorescence associated with FD105, but not the green, was colocalized with anti-EGFR redlabeled antibody, (c) the green fluorescence of nuclei was significantly more intense in NIH 3T3 cells expressing EGFR or ErbB2 than in their wild-type counterparts (P < 0.05). Similarly, the growth inhibitory potency of AL237 was selectively stronger in the transfectants. In summary, the results suggest that AL237 diffuses into the cells and localizes abundantly in the perinuclear region and partially in the nucleus where it degrades into EGFR and DNA targeting species. This bystander-like effect translates into high levels of DNA damage in the nucleus. Sufficient quinazoline levels are released in the cells to block EGF-induced activation of downstream signaling. Mol Cancer Ther; 9(4); 869-82. ©2010 AACR.

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Section: Introductionmentioning

confidence: 99%

Subcellular Distribution of a Fluorescence-Labeled Combi-Molecule Designed to Block Epidermal Growth Factor Receptor Tyrosine Kinase and Damage DNA with a Green Fluorescent Species

Todorova

Larroque

Dauphin-Pierre

et al. 2010

Molecular Cancer Therapeutics

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“…Further, recent immunohistochemical and in situ hybridization analysis showed that the levels of EGFR and TGF-α mRNA and protein are increased in carcinoma cells compared to benign epithelium (Ching et al, 1993;Glynne-Jones et al, 1996). Overexpression of the EGFR is also associated with a worse clinical prognosis (Gullick, 1991;Modjtahedi and Dean, 1994). To date, all prostate cancer cell lines tested (including DU145, PC3, LNCaP, ALVA101 and ARCaP) express increased EGFRs (Liu et al, 1993;Glynne-Jones et al, 1996;Zhau et al, 1996).…”

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confidence: 99%

Complex post-transcriptional regulation of EGF-receptor expression by EGF and TGF-α in human prostate cancer cells

et al. 1999

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SummaryThe epidermal growth factor receptor (EGFR) plays an important role in the development and progression of prostate cancer and its overexpression is associated with decreased survival. With progression, prostate cancer cells switch from epidermal growth factor (EGF) to transforming growth factor α (TGF-α) synthesis, which contributes to autocrine growth and unrestrained proliferation. To define the molecular mechanisms involved in the regulation of EGFR expression by EGF and TGF-α we studied three human prostate cancer cell lines, androgen-responsive (LNCaP) and -unresponsive (DU145 and PC3). Here we show that TGF-α stabilized EGFR mRNA two-to threefold in all three cell lines, whilst EGF stabilized EGFR mRNA ~ twofold in LNCaP and DU145 cells, but not in PC3 cells. Both ligands increased EGFR transcription in LNCaP and DU145 cells, with less effect in PC3 cells. In all three cell lines EGF reduced total EGFR protein levels more than TGF-α, but this was associated with a greater increase in de novo protein synthesis with EGF compared to TGF-α. Only EGF, however, shortened EGFR protein stability (half-life decreased from 5 h to 120 min), resulting in rapid disappearance of newly synthesized EGFR protein. Both ligands increased total LNCaP and DU145 cell numbers. These studies demonstrate that the EGF-and TGF-α-induced upregulation of EGFR mRNA and protein in human prostate cancer cell lines is complex and occurs at multiple, transcriptional and post-transcriptional levels. Taken together, these data provide novel insight into the molecular mechanisms by which TGF-α would preferentially maintain an autocrine loop in human prostate cancer cells. Furthermore, this work suggests that in human prostate cancer cells ligand-specific differential intracellular trafficking of the EGFR plays a major role in regulating its expression.

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“…More importantly, EGFR expression in human breast tumours has been correlated with a poor prognosis (Perez et al, 1984;Sainsbury et al, 1985;Received 17April 1996Revised 7 August 1996 Accepted 8 August 1996 Correspondence to: R Perez and F-D Bohmer Macias et al, 1986Macias et al, , 1987aKlijn et al, 1992), and a link between EGFR activity and the malignant process has also been suggested for a number of other epithelial tumours, including non-small-cell lung cancer (NSCLC) (Khazaie et al, 1993;Modjtahedi and Dean, 1994;Fontanini et al, 1995). Therefore, the evaluation of the EGF/EGFR system as a potential target for tumour therapy is highly warranted (Baselga and Mendelsohn, 1994a;Modjtahedi and Dean, 1994). Different strategies have been employed to block EGFR signalling.…”

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confidence: 99%

Growth inhibition of human lung adenocarcinoma cells by antibodies against epidermal growth factor receptor and by ganglioside GM3: involvement of receptor-directed protein tyrosine phosphatase(s)

Pestana

Greiser²,

Sánchez³

et al. 1997

Br J Cancer

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Summary Growth of the EGF receptor-expressing non-small-cell lung carcinoma cell line H125 seems to be at least partially driven by autocrine activation of the resident EGF receptors. Thus, the possibility of an EGF receptor-directed antiproliferative treatment was investigated in vitro using a monoclonal antibody (cxEGFR ior egf/r3) against the human EGF receptor and gangliosides which are known to possess antiproliferative and anti-tyrosine kinase activity. The moderate growth-inhibitory effect of aEGFR ior egf/r3 was strongly potentiated by the addition of monosialoganglioside G M3 Likewise, the combination of aEGFR ior egf/r3 and GM3 inhibited EGF receptor autophosphorylation activity in Hi 25 cells more strongly than either agent alone. A synergistic inhibition of EGF receptor autophosphorylation by aEGFR ior egf/r3 and GM3 was also observed in the human epidermoid carcinoma cell line A431. In both cell lines, the inhibition of EGF receptor autophosphorylation by GM3 was prevented by pretreatment of the cells with pervanadate, a potent inhibitor of protein tyrosine phosphatases (PTPases). Also, GM3 accelerated EGF receptor dephosphorylation in isolated A431 cell membranes. These findings indicate that GM3 has the capacity to activate EGF receptor-directed PTPase activity and suggest a novel possible mechanism for the regulation of cellular PTPases.

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The Receptor for Egf and Its Ligands - Expression, Prognostic Value and Target for Therapy in Cancer (Review)

Cited by 78 publications

References 0 publications

Subcellular Distribution of a Fluorescence-Labeled Combi-Molecule Designed to Block Epidermal Growth Factor Receptor Tyrosine Kinase and Damage DNA with a Green Fluorescent Species

Subcellular Distribution of a Fluorescence-Labeled Combi-Molecule Designed to Block Epidermal Growth Factor Receptor Tyrosine Kinase and Damage DNA with a Green Fluorescent Species

Complex post-transcriptional regulation of EGF-receptor expression by EGF and TGF-α in human prostate cancer cells

Growth inhibition of human lung adenocarcinoma cells by antibodies against epidermal growth factor receptor and by ganglioside GM3: involvement of receptor-directed protein tyrosine phosphatase(s)

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