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

Zhang, Yuxiang; Banerjee, Sanjeev; Wang, Zhiwei; Marciniak, Dorota; Sarkar, Fazlul H.

doi:10.1158/0008-5472.can-04-3654

Cited by 28 publications

(37 citation statements)

References 16 publications

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“…ERRP, a recently isolated pan-erbB inhibitor, possesses substantial homology with the extracellular ligandbinding domain of EGFR and its family members (8). Previously, we reported that ERRP inhibited cell growth of pancreatic cancer cells by attenuating EGFR activation in vitro and in vivo (13,14). Our current data show that ERRP not only inhibits cell growth but also induces apoptotic cell death of pancreatic cancer cells, similar observations in colon and breast cancer cells (24).…”

Section: Discussionsupporting

confidence: 85%

“…ERRP fusion protein was generated using the Drosophila expression system (Invitrogen) as described previously, and silver staining of the SDS-PAGE resulted in a predominant protein band of M r 53 to 55 following purification (13,14). The protein band of M r 53 to 55 corresponded well with the calculated molecular mass of ERRP, which is composed of 479 amino acids.…”

Section: Methodsmentioning

confidence: 95%

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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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Section: Discussionsupporting

confidence: 85%

Section: Methodsmentioning

confidence: 95%

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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“…Most importantly, ERRP was found to inhibit pancreatic tumor growth in a SCID mouse xenograft model. The anti-tumor activity of ERRP correlated well with down-regulation of NF-κB, MAPK, Akt, and Notch-1 (Wang et al, 2006b;Zhang et al, 2005;Zhang et al, 2006). ERRP also down-regulates NF-κB downstream genes such as VEGF and MMP-9, and inhibits cancer cell invasion, suggesting that ERRP could be a very potent agent for the treatment of pancreatic cancer by inhibiting cell survival signaling, tumor growth, invasion, and angiogenesis.…”

Section: New Strategies For the Treatment Of Pancreatic Cancers Targementioning

confidence: 83%

Pancreatic cancer: Pathogenesis, prevention and treatment

Sarkar

Banerjee

2007

Toxicology and Applied Pharmacology

104

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Pancreatic cancer is the fourth leading cause of cancer death in the United States with a very low survival rate of 5 years. To better design new preventive and/or therapeutic strategies for the fight against pancreatic cancer, the knowledge of the pathogenesis of pancreatic cancer at the molecular level is very important. It has been known that the development and the progression of pancreatic cancer are caused by the activation of oncogenes, the inactivation of tumor suppressor genes, and the deregulation of many signaling pathways among which the EGFR, Akt, and NF-κB pathways appear to be most relevant. Therefore, the strategies targeting EGFR, Akt, NF-κB, and their downstream signaling could be promising for the prevention and/or treatment of pancreatic cancer. In this brief review, we will summarize the current knowledge regarding the pathogenesis, prevention, and treatment of pancreatic cancer.

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“…It remains to be determined if this difference is a time-dependent phenomenon, and whether a longer treatment period (more than the 10 days used in the present study) would result in down-regulation of other members of the EGFR family. However, the overexpression of EGFR in carcinogen-treated mucosa (29,38), ACF (32), and Min intestinal tissue (33) suggests that this receptor plays a crucial role in the development of colon cancer.…”

Section: Discussionmentioning

confidence: 99%

“…Previously, we reported that increased activation of EGFR in the colonic mucosa of aged or carcinogen-treated rodents was associated with elevated levels of membrane-bound precursor forms of TGF-a (29,38), which was thought to be involved in activating the intrinsic EGFR activity through an autocrine/ juxtacrine mechanism (45,46). The substantial homology of ERRP to the extracellular ligand-binding domain of the EGFRs allows for sequestration of ligands, rendering them unavailable for binding to and activation of the receptors.…”

Section: Discussionmentioning

confidence: 99%

Regression of Early and Intermediate Stages of Colon Cancer by Targeting Multiple Members of the EGFR Family with EGFR-Related Protein

Schmelz

Sengupta

et al. 2007

Cancer Research

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A role of the epidermal growth factor receptor (EGFR) family has been suggested in colon cancer etiology, progression, and/ or severity. Our recently identified pan-erbB inhibitor EGFRrelated protein (ERRP) targets EGFRs by attenuating their activation and subsequent signaling leading to cellular growth inhibition. In the present study, we evaluated the therapeutic effectiveness of ERRP on early and intermediate stages of colon cancer by examining regression of chemically induced aberrant crypt foci (ACF) in the colon of CF1 mice and intestinal adenomas in APC Min+/À (Min) mice. After formation of ACF or adenomas, the mice were injected (i.p.) with ERRP (50 Mg/mouse) for 10 consecutive days. This treatment significantly reduced the number of ACF from 25.0 F 3.0 (controls) to 14.9 F 1.6 (ERRP-treated; P = 0.011) and also reduced their size (P < 0.01). In Min mice, ERRP caused the regression of adenomas throughout the small intestine (P < 0.05) and reduced their size (P < 0.001). This could partly be attributed to inhibition of proliferation and stimulation of apoptosis in the intestinal mucosa and was associated with decreased activation of several EGFR family members, suppression of downstream effector nuclear factor KB and down-regulation of cyclooxygenase-2. ERRP-induced attenuation of EGFR activation could be due to increased sequestration of the ligand(s) by ERRP, rendering them unavailable for binding to and activation of the receptor. In conclusion, our data show that ERRP is effective in regressing both early and intermediate intestinal lesions and could be an effective therapeutic agent for colon cancer. [Cancer Res 2007;67(11):5389-96]

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

Cited by 28 publications

References 16 publications

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

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

Pancreatic cancer: Pathogenesis, prevention and treatment

Regression of Early and Intermediate Stages of Colon Cancer by Targeting Multiple Members of the EGFR Family with EGFR-Related Protein

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