Reorganization of ErbB Family and Cell Survival Signaling after Knock-down of ErbB2 in Colon Cancer Cells

Hu, Yi; Venkateswarlu, Somepalli; Sergina, Natalia; Howell, Gillian; Clair, Patricia St.; Humphrey, Lisa E.; Li, Wenhui; Hauser, Jennie; Zborowska, Elizabeth; Willson, James K.V.; Brattain, Michael G.

doi:10.1074/jbc.m414238200

Cited by 21 publications

(24 citation statements)

References 63 publications

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“…In addition to this escape from inhibition of signal transduction through a mechanism involving incomplete inhibition of a heterodimerized receptor, we have shown that inhibition of one receptor can be compensated for by the increased expression and activation of another receptor (36). ErbB2 inactivation by stable transfection of a single chain antibody against ErbB2 resulted in the inactivation of ErbB2 tyrosine phosphorylation and reduced heterodimerization of ErbB2 and ErbB3.…”

Section: Discussionmentioning

confidence: 99%

A Novel Mechanism of Resistance to Epidermal Growth Factor Receptor Antagonism In vivo

et al. 2007

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Epidermal growth factor receptor (EGFR) is widely expressed in a number of solid tumors including colorectal cancers. Overexpression of this receptor is one means by which a cell can achieve positive signals for survival and proliferation; another effective means is by constitutive activation of EGFR. We have elucidated the role of constitutive EGFR signaling in malignant progression by stably transfecting colon cancer cells with a human transforming growth factor-A cDNA (a ligand for EGFR) under repressible control by tetracycline. We show that constitutive expression of transforming growth factor-A and its subsequent constitutive activation of EGFR allows for cancer cell survival in response to environmental stress in vitro and in vivo as well. The reversal of constitutive EGFR activation results in the loss of downstream mitogenactivated protein kinase and Akt activation, and a reduction in xenograft size that is associated with decreased proliferation and increased apoptosis. We used CI-1033, a small molecule antagonist of EGFR, to dissect an activation pathway that shows the ability of ERBb2 to activate Akt, but not Erk in the face of EGFR antagonism. This novel escape mechanism is a possible explanation of why anti-EGFR therapies have shown disappointing results in clinical trials. [Cancer Res 2007;67(2):665-73]

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Section: Discussionmentioning

confidence: 99%

A Novel Mechanism of Resistance to Epidermal Growth Factor Receptor Antagonism In vivo

et al. 2007

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“…Similarly, ZD1839, a specific EGFR tyrosine kinase inhibitor, has been reported to inhibit the growth of ErbB2-overexpressing breast cancer cells, possibly by sequestration of ErbB2 and ErbB3 receptors in an inactive heterodimer configuration with EGFR (47). Another group also reported that elimination of ErbB2 signaling resulted in an increase in EGFR expression and activation and that its increased activation contributed to sustained cell survival (48). Changes in receptor-receptor interactions between ErbB family members and compensatory changes in the ErbB family after inhibition of one of its members are of potential importance in optimizing current EGFR family -directed therapies for cancer.…”

Section: Discussionmentioning

confidence: 99%

Growth Stimulation of Non–Small Cell Lung Cancer Cell Lines by Antibody against Epidermal Growth Factor Receptor Promoting Formation of ErbB2/ErbB3 Heterodimers

Maegawa

Takeuchi

Funakoshi

et al. 2007

Molecular Cancer Research

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Antibodies are the most rapidly expanding class of human therapeutics, including their use in cancer therapy. Monoclonal antibodies (mAb) against epidermal growth factor (EGF) receptor (EGFR) generated for cancer therapy block the binding of ligand to various EGFR-expressing human cancer cell lines and abolish ligand-dependent cell proliferation. In this study, we show that our mAb against EGFRs, designated as B4G7, exhibited a growth-stimulatory effect on various human cancer cell lines including PC-14, a non -small cell lung cancer cell line; although EGF exerted no growth-stimulatory activity toward these cell lines. Tyrosine phosphorylation of EGFRs occurred after treatment of PC-14 cells with B4G7 mAb, and it was completely inhibited by AG1478, a specific inhibitor of EGFR tyrosine kinase. However, this inhibitor did not affect the B4G7-stimulated cell growth, indicating that the growth stimulation by B4G7 mAb seems to be independent of the activation of EGFR tyrosine kinase. Immunoprecipitation with anti-ErbB3 antibody revealed that B4G7, but not EGF, stimulated heterodimerization between ErbB2 and ErbB3. ErbB3 was tyrosine phosphorylated in the presence of B4G7 but not in the presence of EGF. Further, the phosphorylation and B4G7-induced increase in cell growth were inhibited by AG825, a specific inhibitor of ErbB2. These results show that the ErbB2/ErbB3 dimer functions to promote cell growth in B4G7-treated cells. Changes in receptor-receptor interactions between ErbB family members after inhibition of one of its members are of potential importance in optimizing current EGFR family -directed therapies for cancer. (Mol Cancer Res 2007;5(4):393 -401)

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“…Integrin β4 signaling also promotes ErbB2-mediated cell proliferation in a mammary tumor model [32]. Since ErbB2 exerts pro-survival effects in colon carcinoma cell lines [33,34], the effects of PTHrP on colon cancer cell proliferation in vitro and on xenograft growth in vivo may be mediated via the integrin β4/ErbB2 pathway.…”

Section: Discussionmentioning

confidence: 99%

PTHrP increases xenograft growth and promotes integrin α6β4 expression and Akt activation in colon cancer

et al. 2007

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Parathyroid hormone-related protein (PTHrP) is expressed by human colon cancer tissue and cell lines. Expression of PTHrP and phosphatidylinositol 3-kinase (PI3-K) pathway components correlates with the severity of colon carcinoma. Here we observed a positive effect of endogenous PTHrP on LoVo (human colon cancer) cell proliferation, migration, invasion, integrin α6 and β4 expression, and p-Akt levels. There was a direct correlation between PTHrP expression and anchorage-independent cell growth. PTHrP significantly increased xenograft growth; tumors from PTHrP-overexpressing cells showed increased expression of integrins α6 and β4, and PI3-K pathway components. The higher expression of PTHrP in human colon cancer adenocarcinoma vs. normal colonic mucosa was accompanied by increased integrin α6 and β4 levels. Elevated PTHrP expression in colon cancer may thus upregulate integrin α6β4 expression, with consequent PI3-K activation. Targeting PTHrP might result in effective inhibition of tumor growth, migration and invasion.

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Reorganization of ErbB Family and Cell Survival Signaling after Knock-down of ErbB2 in Colon Cancer Cells

Cited by 21 publications

References 63 publications

A Novel Mechanism of Resistance to Epidermal Growth Factor Receptor Antagonism In vivo

A Novel Mechanism of Resistance to Epidermal Growth Factor Receptor Antagonism In vivo

Growth Stimulation of Non–Small Cell Lung Cancer Cell Lines by Antibody against Epidermal Growth Factor Receptor Promoting Formation of ErbB2/ErbB3 Heterodimers

PTHrP increases xenograft growth and promotes integrin α6β4 expression and Akt activation in colon cancer

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