EGF receptor-related protein (ERRP) inhibits invasion of colon cancer cells and tubule formation by endothelial cells in vitro.
Activation of the epidermal growth factor receptor (EGFR) and/or its family member(s) stimulates many processes of carcinogenesis, including cell invasion and the formation of new blood vessels, events that are critically involved in angiogenesis. Interference with the activation of EGFRs, therefore, represents a promising strategy for the development of novel and selective anticancer therapies. Previously, we reported that EGFR-related protein (ERRP), which we have isolated and characterized as a pan-erbB inhibitor, is a potential therapeutic agent for colorectal and other epithelial cancers. The present investigation was undertaken to determine whether ERRP would affect the invasion of colon cancer cells and formation of tubules, and the regulation of these processes. ERRP inhibited tubule formation by aortic endothelial cells and invasion of HCT-116 colon cancer cells through matrigel. These changes were associated with marked reductions in the synthesis and secretion of bFGF, VEGF and TGF-alpha by HCT-116 cells. Secretion of bFGF and VEGF by aortic endothelial cells was also inhibited by ERRP. Microarray analysis of ERRP-treated HCT-116 cells showed reduced levels of several growth regulatory proteins such as p21Rac1, Stratifin (14-3-3 Sigma), focal adhesion kinase (FAK) and mediators of the Ras-Raf-ERK pathway. ERRP treatments resulted in reduced expression of p21Rac1 and inhibited the constitutive activation of FAK and MEK2 in HCT-116 cells. Transfection of constitutively activate p21Rac1 or MEK2 into HCT-116 cells abrogated ERRP-induced inhibition of growth. In summary, it was demonstrated that ERRP not only inhibits cell growth, but also the processes of cell invasion and blood vessel formation that are critical for the development and progression of carcinogenesis.
Rishi
Arun K
AK
Veterans Affairs Medical Center, Detroit, Michigan 48201, USA.
Parikh
Rakesh
R
Wali
Anil
A
Durko
Lukasz
L
Zhang
Liyue
L
Yu
Yingjie
Y
Majumdar
Adhip P N
AP
D048948:14-3-3 Proteins; D014408:Biomarkers, Tumor / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D002196:Capillaries / Q000187:drug effects / Q000254:growth & development; D003110:Colonic Neoplasms / Q000098:blood supply* / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D019926:Cyclin B / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D056744:Cyclin B1; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects*; D004789:Enzyme Activation; D066246:ErbB Receptors; D005092:Exonucleases / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D005095:Exoribonucleases; D048049:Extracellular Signal-Regulated MAP Kinases / Q000096:biosynthesis / Q000378:metabolism; D051417:Focal Adhesion Kinase 1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D006023:Glycoproteins / Q000494:pharmacology*; D045325:HCT116 Cells; D006801:Humans; D048369:MAP Kinase Kinase 1 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D011994:Recombinant Proteins / Q000494:pharmacology; D054462:p21-Activated Kinases
D048948:14-3-3 Proteins; D014408:Biomarkers, Tumor; C534699:CCNB1 protein, human; D019926:Cyclin B; D056744:Cyclin B1; D006023:Glycoproteins; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D011994:Recombinant Proteins; C512478:EGFR protein, human; D066246:ErbB Receptors; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human; C515903:PAK1 protein, human; D017346:Protein Serine-Threonine Kinases; D054462:p21-Activated Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D048369:MAP Kinase Kinase 1; C482125:MAP2K1 protein, human; D005092:Exonucleases; D005095:Exoribonucleases; C413442:SFN protein, human