Antitumor activity of epidermal growth factor receptor-related protein is mediated by inactivation of ErbB receptors and nuclear factor-kappaB in pancreatic cancer.
The erbB family of receptor tyrosine kinases plays critical roles in human cancers, including pancreatic cancer. Discovering a specific agent, which targets multiple members of the erbB family, would be important in pancreatic cancer therapy. Recently, we isolated a novel negative regulator of epidermal growth factor receptor (EGFR), termed EGFR-related protein (ERRP), whose expression attenuates EGFR activation. In the current study, we examined the effects of recombinant ERRP on the growth and ligand-induced activation of multiple members of erbB family in three pancreatic cancer cell lines that express varying levels of EGFR and other member(s) of its family, specifically HER-2. Additionally, we compared the growth inhibitory effect of ERRP with that of Erbitux or Herceptin. Our results showed that ERRP is most effective in inhibiting proliferation of BxPC-3, HPAC, and PANC-1 pancreatic cancer cells. ERRP also inhibited ligand-induced activation of EGFR, HER-2, and HER-3 (ErbB3). In contrast, Erbitux and Herceptin only partially or modestly inhibited activation of EGFR, HER-2, and HER-3. Most importantly, ERRP was found to inhibit pancreatic tumor growth in a severe combined immunodeficient mouse xenograft model. The antitumor activity of ERRP correlates well with tumor differentiation and down-regulation of nuclear factor-kappaB activity. In summary, our results suggest that ERRP is an effective pan-erbB inhibitor, which could be a potential therapeutic agent for pancreatic cancers expressing different levels and subclasses of erbB family of proteins.
Zhang
Yuxiang
Y
Department of Pathology, Karmanos Cancer Institute, Wayne State University of Medicine, Detroit, MI 48201, USA.
Banerjee
Sanjeev
S
Wang
Zhiwei
Z
Xu
Hu
H
Zhang
Liyue
L
Mohammad
Ramzi
R
Aboukameel
Amro
A
Adsay
Nazmi V
NV
Che
Mingxin
M
Abbruzzese
James L
JL
Majumdar
Adhip P N
AP
Sarkar
Fazlul H
FH
D002454:Cell Differentiation; D049109:Cell Proliferation; D015536:Down-Regulation; D066246:ErbB Receptors / Q000096:biosynthesis* / Q000502:physiology*; D006023:Glycoproteins / Q000502:physiology*; D006801:Humans; D008024:Ligands; D016328:NF-kappa B / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000201:enzymology / Q000473:pathology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis; D011994:Recombinant Proteins; D014407:Tumor Cells, Cultured
D066246:ErbB Receptors; D006023:Glycoproteins; D008024:Ligands; D016328:NF-kappa B; D018719:Erb-b2 Receptor Tyrosine Kinases; D011994:Recombinant Proteins; C512478:EGFR protein, human