Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04626 (erbB-2)
 5,251 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We previously reported that exposure of DiFi human colon cancer cells to the anti-epidermal growth factor (EGF) receptor monoclonal antibody (mAb) 225 resulted in apoptosis, but the mechanisms remain to be elucidated. In the present study, we investigated the effects of a panel of four anti-EGF receptor mAbs, each of which binds to different epitopes of the EGF receptor in DiFi cells, on the induction of apoptosis. We found that each of these mAbs induced apoptosis in DiFi cells. Exposure of DiFi cells to mAb 225 activated the initiation caspase-8, which was detectable between 8 and 16 h after exposure of the cells to the antibody. There was also an activation of the initiation caspase-9, which lagged a few hours behind the activation of caspase-8. Exposure of DiFi cells to mAb 225 also activated the execution caspase-3, which was accompanied temporally by evidence of cleavage of a well-characterized caspase-3 substrate, poly(ADP)ribosepolymerase (PARP). Pre-exposure of the cells to the caspase-3-specific inhibitor DEVD-CHO partially reduced the mAb 225-induced PARP cleavage and apoptosis, whereas pre-exposure of the cells to the caspase pan-inhibitor z-VAD-fmk completely inhibited mAb 225-induced apoptosis. Caspases-3, -8 and -9 were not activated in the cell lines in which mAb 225 only induced G1 phase arrest of the cell cycle. In contrast to the apoptosis of DiFi cells induced by ultraviolet irradiation, which strongly activated the c-jun N-terminal kinase-1 (JNK1) and the caspase cascade, mAb 225-induced apoptosis and activation of the caspase cascade in DiFi cells were not associated with activation of JNK1.
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PMID:Induction of apoptosis and activation of the caspase cascade by anti-EGF receptor monoclonal antibodies in DiFi human colon cancer cells do not involve the c-jun N-terminal kinase activity. 1086 8

Survival of cancer cells in response to therapy, immune response, or metastasis depends on interactions between pro- and antiapoptotic signals. Two major proapoptotic pathways have been described: (a) a death receptor pathway; and (b) a mitochondrial pathway. We reported previously that Akt and the epidermal growth factor (EGF) receptor send separate, redundant survival signals that act to inhibit the mitochondrial proapoptotic pathway in prostate cancer LNCaP cells. However, it was unclear at what level the pro- and antiapoptotic signals interact in these cells, and it was also unclear whether these signals would inhibit the death receptor pathway. We found that EGF can protect LNCaP cells from apoptosis induced by LY294002 but not from tumor necrosis factor a (TNF-alpha)-induced apoptosis. Furthermore, TNF-alpha induced apoptosis under conditions in which Akt was active. Treatment with TNF-alpha resulted in activation of caspase 8 and cleavage of BID, which in turn induced cytochrome c release and caspase 9-dependent activation of effector caspases. Thus, proapoptotic signals induced by both TNF-alpha and LY294002 converge on mitochondria and trigger cytochrome c release. Because EGF can inhibit cytochrome c release induced by LY294002 but not cytochrome c release induced by TNF-alpha, we suggest that the EGF survival mechanism operates on the mitochondrial pathway at a site upstream of cytochrome c release. The ability of TNF-alpha to bypass survival signals from activated EGF receptor and Akt in prostate cancer cells makes death receptor signaling a promising avenue for therapeutic intervention.
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PMID:Tumor necrosis factor alpha induces BID cleavage and bypasses antiapoptotic signals in prostate cancer LNCaP cells. 1128 52

We previously reported that the anti-epidermal growth factor (EGF) receptor monoclonal antibody (mAb) 225 induces DiFi colon cancer cells to undergo apoptosis, and this apoptosis was accompanied by activation of the two apoptosis initiation caspases, caspase-8 and caspase-9. In the current study, we found that pretreatment of DiFi cells with the caspase-8-specific inhibitor z-IETD-fmk but not pretreatment with the caspase-9-specific inhibitor z-LEHD-fmk inhibited mAb 225-induced apoptosis, indicating that caspase-8 plays an essential role in initiating mAb 225-induced apoptosis. Because caspase-8 is activated primarily by the members of the tumor necrosis factor (TNF) receptor family, such as Fas, TNF receptor-1 (TNFR1), or receptors for TNF-related apoptosis-inducing ligand (TRAIL), we investigated whether mAb 225 activated caspase-8 by regulating one or more of these known pathways. Exposure of DiFi cells to TNFalpha or TRAIL activated caspase-8 and induced apoptosis in the cells. A TNFR1-antagonistic mAb or a TRAIL decoy receptor inhibited the activation of caspase-8 and the subsequent apoptosis induced by TNFalpha or TRAIL, respectively, in the cells. However, neither the TNFR1-antagonistic mAb nor the TRAIL decoy receptor inhibited mAb 225-induced activation of caspase-8 and apoptosis in DiFi cells. DiFi cells express detectable level of Fas but are not sensitive to the treatment by the Fas-agonistic mAb CH-11. A Fas-antagonistic mAb (ZB-4) inhibited the Fas-agonistic mAb CH-11-induced caspase-8 activation and apoptosis in Jurkat T-leukemic cells (used as positive control), but had no effect on mAb 225-induced activation of caspase-8 and apoptosis in DiFi cells. Taken together, our results suggest that mAb 225 does not interact with or regulate these known death receptor pathways. An exploration is therefore warranted for a novel mechanism by which mAb 225 activates caspase-8 and triggers apoptosis in DiFi cells.
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PMID:The monoclonal antibody 225 activates caspase-8 and induces apoptosis through a tumor necrosis factor receptor family-independent pathway. 1143 35

The oncoprotein HER-2/neu is a prosurvival factor, and its overexpression has been correlated with poor prognosis in patients with breast cancer. We report that HER-2 is a new substrate for caspase-8 and that tumor necrosis factor alpha (TNF-alpha) stimulation leads to an early caspase-8-dependent HER-2 cleavage in MCF7 A/Z breast adenocarcinoma cells defective for nuclear factor kappaB (NFkappaB) activation. We show that the antiapoptotic transcription factor NFkappaB counteracts this cleavage through induction of the caspase-8 inhibitor c-FLIP. Our results also demonstrate that this HER-2 cleavage contributes to the TNF-alpha-induced apoptosis pathway because ectopic expression of an uncleavable HER-2 protects NFkappaB-defective cells against TNF-alpha-mediated cell death. Therefore, we propose an original model in which NFkappaB exerts a new antiapoptotic function by counteracting TNF-alpha-triggered cleavage of the HER-2 survival factor.
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PMID:Caspase-8-dependent HER-2 cleavage in response to tumor necrosis factor alpha stimulation is counteracted by nuclear factor kappaB through c-FLIP-L expression. 1508 80

Overexpression of HER-2/neu confers cellular resistance to tumor necrosis factor (TNF)-mediated cytotoxicity to SKBR-3 breast cancer cell lines. To understand the correlation between HER-2/neu expression and TNF resistance, we examined the unique signaling pathways associated with the cytotoxic effects of the immunocytokine scFv23/TNF, recombinant single-chain antibody fusion constructs containing TNF and targeting HER-2/neu, in TNF-resistant SKBR-3-LP cells. We found that treatment of HER-2/neu-overexpressing SKBR-3-LP cells with scFv23/TNF resulted in a 5- to 7-fold higher level of TNF receptor-1 expression 48 hours after exposure. In addition, treatment of SKBR-3-LP cells with scFv23/TNF resulted in down-regulation of Akt phosphorylation and induced apoptosis through cleavage of caspase-8, caspase-3, and poly(ADP-ribose) polymerase. ScFv23/TNF-induced cytotoxicity was inhibited by blocking of the binding of the TNF component of scFv23/TNF to TNF receptor-1 and was dependent on activation of caspase-8 and caspase-3. These results indicate that the immunocytokine scFv23/TNF sensitizes TNF-resistant HER-2/neu-overexpressing SKBR-3-LP cells to TNF-induced apoptosis via the overexpression of TNF receptor-1 and suggest that the overexpression of TNF receptor-1 plays a crucial role in TNF sensitivity in HER-2/neu-overexpressing cancer cells. ScFv23/TNF targeting the HER-2/neu may be an effective cytotoxic agent against HER-2/neu-overexpressing cancer cells, which are inherently resistant to TNF.
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PMID:The immunocytokine scFv23/TNF sensitizes HER-2/neu-overexpressing SKBR-3 cells to tumor necrosis factor (TNF) via up-regulation of TNF receptor-1. 1609 36

The epidermal growth factor (EGF) receptor (EGFR) plays an important role in the growth and progression of breast cancer. Overexpression of EGFR or the high activity of EGFR signal pathway has been related with increases in cell proliferation and a poor prognosis in patients with breast cancer. Several human breast cancer cell lines depend on estrogen for their proliferation. EGF may bypass the requirement of estrogen for the proliferation of breast cancer cells. To evaluate this hypothesis, MCF-7 breast cancer cells were stimulated with EGF and the effects on cell proliferation, signal pathways, and cell cycle progression were determined. The results demonstrate that EGF stimulation in the absence of others growth factors induced a modest effect on cell proliferation and the induction of a cellular arrest in the G(1) phase of the cell cycle. Although phosphorylation of AKT and ERK proteins were detected, this phosphorylation was insufficient to support of cell cycle progression. Cellular arrest in G(1) phase was accompanied by an increase in p21(CIP1) protein, down regulation of the BCL-2 protein, induction of caspase-8, and ARHI/NOEY2 an imprinted tumor suppressor gene. These results indicate that EGFR activation by itself is not sufficient for the proliferation of breast cancer cells and suggest the existence of a mechanism that induces apoptosis upon EGFR activation.
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PMID:Cell death of MCF-7 human breast cancer cells induced by EGFR activation in the absence of other growth factors. 1686 4

Leukotrienes (LTs) and lipoxins (LXs) are lipid mediators that play a key role in regulating acute inflammatory responses. Their roles in neural stem cell (NSC) functions are of interest. We showed here that LTB(4) and LXA(4) regulated proliferation and differentiation of murine NSCs that were isolated from embryo brains. Proliferation of NSCs was stimulated by LTB(4) (3 to 100 nM) and blocked by receptor antagonist (IC(50)=2.7 microM). In contrast, LXA(4), and its aspirin-triggered-15-epi-LXA(4) stable analog attenuated growth of NSCs at as little as 1 nM. Both lipoxygenase (LOX) inhibitors and LTB(4) receptor antagonists caused apoptosis and cell death. Gene chip analysis revealed that growth-related gene expressions such as epidermal growth factor (EGF) receptor, cyclin E, p27, and caspase 8 were tightly regulated by LTB(4); LXA(4) gave the opposite gene expressions. In addition to proliferation, LTB(4) induced differentiation of NSCs into neurons as monitored by neurite outgrowth and MAP2 expression. These results indicate for the first time that LTB(4) and LXA(4) directly regulate proliferation and differentiation of NSCs, suggesting these new pathways may be useful in restoring stem cells.
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PMID:Leukotriene B4 and lipoxin A4 are regulatory signals for neural stem cell proliferation and differentiation. 1694 Jan 50

Human pancreatic tumor cells are highly resistant to both tumor necrosis factor (TNF) and to chemotherapeutic agents. HER-2/neu expression has been proposed as a negative prognostic marker in pancreatic intraepithelial neoplasia. Our approach was to utilize HER-2/neu expression on the surface of tumor cells as a therapeutic target employing scFv23/TNF, immunocytokine composed of a single chain Fv antibody (scFv23) targeting the HER-2/neu and the cytokine TNF as the cytotoxic moiety, to deliver TNF directly to TNF-resistant pancreatic tumor cells. Using a panel of human pancreatic cell lines, which overexpress HER-2/neu, we evaluated the in vitro response of cells to TNF, scFv23/TNF, Herceptin, and a combination of scFv23/TNF with various chemotherapeutic agents. We found that all pancreatic cancer cell lines were highly resistant to the cytotoxic effects of TNF and that scFv23/TNF was highly cytotoxic to TNF-resistant HER-2/neu-expressing pancreatic cancer cell lines at levels rivaling that of conventional chemotherapeutic agents. Combination studies demonstrated a synergistic cytotoxic effect of scFv23/TNF with 5-fluorouracil (5-FU) in TNF-resistant pancreatic cancer cell lines. Mechanistic studies demonstrated that the 5-FU plus scFv23/TNF combination specifically resulted in a down-regulation of HER-2/neu, p-Akt and Bcl-2 and up-regulation of TNF-R1. In addition, the combination 5-FU plus scFv23/TNF induced apoptosis and this synergistic effect was dependent on activation of caspase-8 and caspase-3. Delivery of the cytokine TNF to HER-2/neu expressing pancreatic tumor cells, which are inherently resistant to TNF using scFv23/TNF may be an effective therapy for pancreatic cancer especially when utilized in combination with 5-FU.
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PMID:The immunocytokine scFv23/TNF targeting HER-2/neu induces synergistic cytotoxic effects with 5-fluorouracil in TNF-resistant pancreatic cancer cell lines. 1808 72

Expression of estrogen (ER) and progesterone receptors, c-erbB-2 oncogene, mutant p53 antioncogene (mp53), e-cadherin adhesion, and apoptotic caspase-8 antigens in tumor relative to matched normal tissue specimens from 102 unselected patients with primary ductal breast carcinoma of various tumor grades was assessed by immunohistochemistry and correlated with patient's biologic and clinical features, such as age, menstrual status, age of menarche, tumor grade and diameter, the presence or absence of metastases, and number of infiltrated lymph nodes. We observed association of e-cadherin adhesion, ER and progesterone antigen marker expression with low histologic grade tumors and limited number of lymph node metastases and of c-erbB-2, mp53, and casp-8 antigen marker expression with high histologic grade tumors and increased number of lymph node metastases. We also observed strong correlation (P<0.05) between 4 of the 6 biomarkers and 4 of the 7 patient/tumor parameters examined. Our findings support the hypothesis of independent expression of these 4 strong biomarkers and reveal that nearly 40% of all breast tumor cases studied express similar proportions of 2 major phenotypic combinations [ER/c-erbB-2/mp53/casp-8: +/+/-/+ (19.6%) & +/-/-/+ (17.8%)]. We conclude that, in agreement with earlier reports, our findings support the diagnostic and potential prognostic value of these markers in the clinical assessment of breast cancer.
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PMID:Expression of 6 common antigenic markers in invasive ductal breast carcinoma: potential clinical implications. 2072 20