Epidermal growth factor receptor-related protein: a potential therapeutic agent for colorectal cancer

Marciniak, Dorota; Moragoda, Lathika; Mohammad, Ramzi M.; Yu, Yingjie; Nagothu, Kiran K.; Aboukameel, Amro; Sarkar, Fazlul H.; Adsay, Volkan; Rishi, Arun K.; Majumdar, Adhip P.N.

doi:10.1016/s0016-5085(03)00264-6

Cited by 29 publications

(67 citation statements)

References 23 publications

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“…Briefly, rabbits were immunized by using an epitope from the ''U'' region of ERRP comprising 15 amino acids (AVTRPLHPLAQNRVS) that showed no homology with any known sequence in the database. Western blot analysis of rat liver and gastric mucosa revealed that ERRP antibodies cross-reacted strongly to a protein with molecular mass of f55 kDa, which corresponds well with the calculated molecular mass of ERRP (11). No cross-reactivity with any member of the EGFR family of proteins (170-190 kDa) was observed, suggesting that the antibodies are specific to ERRP.…”

Section: Introductionsupporting

confidence: 64%

“…We recently isolated a novel negative regulator of EGFR, termed EGFR-related protein (ERRP), whose expression seems to attenuate EGFR activation (10). We have observed that recombinant ERRP inhibits the growth of colon cancer cell lines HCT-116 and Caco-2 in vitro and in vivo (11,12). We have also found that ERRP is expressed in most benign pancreatic ductal epithelium and islet cells, but not in normal acinar cells (13).…”

Section: Introductionmentioning

confidence: 99%

“…Polyclonal antibodies against ERRP were generated as previously described (11). Briefly, rabbits were immunized by using an epitope from the ''U'' region of ERRP comprising 15 amino acids (AVTRPLHPLAQNRVS) that showed no homology with any known sequence in the database.…”

Section: Introductionmentioning

confidence: 99%

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Epidermal Growth Factor Receptor–Related Protein Inhibits Cell Growth and Induces Apoptosis of BxPC3 Pancreatic Cancer Cells

et al. 2005

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Dysregulation of the epidermal growth factor receptor (EGFR) signaling network has been frequently reported in pancreatic cancer. Inhibition of EGFR was associated with antitumor effects in both in vitro and in vivo studies of pancreatic cancer. We have previously reported the isolation and characterization of an EGFR-related protein (ERRP), which seems to be a negative regulator of EGFR. In the present investigation, we tested our hypothesis whether recombinant ERRP could be an effective inhibitor of growth of BxPC3 pancreatic cancer cells. Cell growth and apoptosis were measured using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and apoptosis ELISA assay, respectively, in the presence and absence of recombinant ERRP in BxPC3 cells. To evaluate activation of EGFR and its downstream signaling events, levels of phospho-EGFR, phospho-AKT, and phospho-extracellular signal-regulated kinase (phospho-ERK) were determined by Western blot analysis. NF-KB activity was measured by electrophoretic mobility shift assay. Our data show, for the first time, that ERRP inhibits the growth of BxPC3 cells in a dose-and time-dependent manner. The EGF or transforming growth factor (TGF)-A-induced stimulation of cell growth and activation of EGFR was also inhibited by ERRP. These changes were accompanied by a concomitant attenuation of activation of mitogen-activated protein (MAP) kinases, AKT, and NF-KB. ERRP also induced apoptosis as evidenced by increased poly(ADP-ribose) polymerase cleavage and reduction in procaspase3. From these results, we conclude that ERRP is a potent inhibitor of growth of BxPC-3 pancreatic cancer cells, which could be due to attenuation of EGFR cellular signaling processes. We also suggest that ERRP could be a potential therapeutic agent for pancreatic cancer. (Cancer Res 2005; 65(9): 3877-82)

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Section: Introductionsupporting

confidence: 64%

Section: Introductionmentioning

confidence: 99%

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Epidermal Growth Factor Receptor–Related Protein Inhibits Cell Growth and Induces Apoptosis of BxPC3 Pancreatic Cancer Cells

et al. 2005

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“…We have found that recombinant ERRP inhibits the growth of a variety of cancer cells, including colon, prostate, and pancreas in vitro and tumor growth in vivo (9)(10)(11)(12). Although there has been rapid progress for elucidating the mechanism of action of ERRP as an antitumor agent, the exact mechanism has not yet been fully established.…”

Section: Introductionmentioning

confidence: 99%

Epidermal Growth Factor Receptor–Related Protein Inhibits Cell Growth and Invasion in Pancreatic Cancer

Wang¹,

Sengupta

Banerjee³

et al. 2006

Cancer Research

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The epidermal growth factor receptor (EGFR) signaling network plays critical roles in human cancers, including pancreatic cancer, suggesting that the discovery of specific agents targeting EGFR would be extremely valuable for pancreatic cancer therapy. EGFR-related protein (ERRP), a recently identified pan-erbB inhibitor, has been shown to inhibit growth and induce apoptosis of pancreatic cancer cells in vitro and tumor growth in a xenograft model. However, the precise molecular mechanism(s) by which ERRP exerts its antitumor activity remains unclear. The current investigation was undertaken to delineate the tumor growth inhibitory mechanism(s) of ERRP in pancreatic cancer cells. Using multiple molecular assays, such as 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, apoptosis, gene transfection, real-time reverse transcription-PCR, Western blotting, invasion, and electrophoretic mobility shift assay for measuring DNA-binding activity of nuclear factor-KB (NF-KB), we found that ERRP caused marked inhibition of pancreatic cancer cell growth. This was accompanied by increased apoptosis and concomitant attenuation of Notch-1 and NF-KB and down-regulation of NF-KB downstream genes, such as matrix metalloproteinase-9 and vascular endothelial growth factor, resulting in the inhibition of pancreatic cancer cell invasion through the Matrigel. We also found that downregulation of Notch-1 by small interfering RNA before ERRP treatment resulted in enhanced cell growth inhibition and apoptosis. Our data suggest that the ERRP-mediated inactivation of EGFR, Notch-1, NF-KB, and its downstream target genes contributed to the inhibition of cell growth and invasion. We conclude that ERRP could be an effective agent for inhibiting tumor growth and invasion for the treatment of pancreatic cancer. (Cancer Res 2006; 66(15): 7653-60)

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“…Our studies show the pan-erbB inhibitory nature of ERRP, which inhibits the growth of human colon-and pancreatic cell-derived tumors (1,2).…”

Section: In Responsementioning

confidence: 61%

Therapeutic potential of epidermal growth factor receptor–related protein

Rishi¹

2006

Molecular Cancer Therapeutics

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In Response:We respectfully disagree with some of the issues raised by Reiter et al. that imply that epidermal growth factor receptor -related protein (ERRP) lacks therapeutic value. Our studies show the pan-erbB inhibitory nature of ERRP, which inhibits the growth of human colon-and pancreatic cell-derived tumors (1, 2).Although the genetic identity of human ERRP is not known, reverse transcription-PCR analyses indicate that the rat ERRP transcript is a 'chimera' formed with EGFR and peptidase D mRNAs (2). The region of ERRP mRNA corresponding to EGFR encodes a polypeptide containing three of the four ectodomains of EGFR. The peptidase D part of the rat ERRP mRNA does not encode peptidase D protein due to a 29-nucleotide insertion at the junction of the EGFR and peptidase D sequences. As a consequence, a frameshift occurs in the peptidase D sequence that results in the presence of 27 new amino acids (termed the 'U' region) at the COOH-terminus of ERRP.The ability of rat ERRP to induce a host antigenic response was examined by analyzing CD69 expression in human peripheral blood lymphocytes in response to recombinant ERRP in vitro (2). CD69 is a member of the natural killer cell gene complex family of signal transducing receptors. Although not expressed in resting lymphocytes, CD69 represents the earliest activation marker, being rapidly induced on the cell surface on stimulation. CD69 expression is thought to be a useful early marker of antigen-or allergen-specific activation of lymphocytes. We observed that whereas concanavalin-A elevated CD69 expression by f33%, recombinant ERRP caused <10% increase compared to the controls (2). The latter increase is thought to be typical of marginal activation, suggesting that ERRP is unlikely to induce aggressive immunologic responses. We also observed that in non -tumor-bearing severe combined immunodeficient mice, recombinant ERRP up to 4 mg/kg produced no signs of toxicity. Thus, we believe that regardless of the genetic identity of ERRP, our studies have provided good evidence that ERRP is an effective pan-erbB inhibitor and therefore remains a potential anticancer agent.

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Epidermal growth factor receptor-related protein: a potential therapeutic agent for colorectal cancer

Cited by 29 publications

References 23 publications

Epidermal Growth Factor Receptor–Related Protein Inhibits Cell Growth and Induces Apoptosis of BxPC3 Pancreatic Cancer Cells

Epidermal Growth Factor Receptor–Related Protein Inhibits Cell Growth and Induces Apoptosis of BxPC3 Pancreatic Cancer Cells

Epidermal Growth Factor Receptor–Related Protein Inhibits Cell Growth and Invasion in Pancreatic Cancer

Therapeutic potential of epidermal growth factor receptor–related protein

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