Relevance of amyloid precursor-like protein 2 C-terminal fragments in pancreatic cancer cells

Haley L. Peters, Amit Tuli, Xiaojian Wang, Cuiling Liu, Zenggang Pan, Michel M Ouellette, Michael A Hollingsworth, Richard G MacDonald, Joyce C Solheim

Research output: Contribution to journalArticle

10 Scopus citations

Abstract

In some cellular systems, particularly neurons, amyloid precursor-like protein 2 (APLP2), and its highly homologous family member amyloid precursor protein (APP), have been linked to cellular growth. APLP2 and APP undergo regulated intramembrane proteolysis to produce C-terminal fragments. In this study, we found comprehensive expression of APLP2 C-terminal fragments in a panel of pancreatic cancer cell lines; however, APP C-terminal fragments were notably limited to the BxPC3 cell line. Extensive glycosaminoglycan modification on APLP2 was also found in the majority of pancreatic cancer cell lines. Glycosaminoglycan-modified and -unmodified APLP2, and particularly APLP2 C-terminal fragments, also demonstrated increased expression in oncogene-transformed pancreatic ductal cells. Additionally, elevated APLP2 levels were confirmed in human pancreatic cancer tissue. Downregulation of APLP2 and APP expression, alone or in combination, caused a decrease in the growth of a pancreatic cancer cell line with representatively low APP C-terminal fragment expression, the S2-013 cell line. Furthermore, we found that treatment with β-secretase inhibitors to block formation of APLP2 C-terminal fragments decreased the growth and viability of S2-013 cells, without affecting the survival of a non-transformed pancreatic ductal cell line. In conclusion, our studies demonstrate that abundant APLP2, but not APP, C-terminal fragment expression is conserved in pancreatic cancer cell lines; however, APP and APLP2 equally regulated the growth of S2-013 pancreatic cancer cells. Chiefly, our discoveries establish a role for APLP2 in the growth of pancreatic cancer cells and show that inhibitors preventing APLP2 cleavage reduce the viability of pancreatic cancer cells.

Original languageEnglish (US)
Pages (from-to)1464-1474
Number of pages11
JournalInternational journal of oncology
Volume41
Issue number4
DOIs
Publication statusPublished - Oct 1 2012

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Keywords

  • Amyloid precursor protein
  • Amyloid precursor-like protein 2
  • Pancreatic cancer
  • β-site APP cleaving enzyme

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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