Inhibition of amyloid precursor protein processing enhances gemcitabine-mediated cytotoxicity in pancreatic cancer cells.

Abstract

Pancreatic adenocarcinoma or pancreatic cancer is often diagnosed at a very late stage at which point treatment options are minimal. Current chemotherapeutic interventions prolong survival marginally, thereby emphasizing the acute need for better treatment options to effectively manage this disease. Studies from different laboratories have shown that the Alzheimer disease-associated amyloid precursor protein (APP) is overexpressed in various cancers but its significance is not known. Here we sought to determine the role of APP in pancreatic cancer cell survival and proliferation. Our results show that pancreatic cancer cells secrete high levels of sAPPα, the α-secretase cleaved ectodomain fragment of APP, as compared with normal non-cancerous cells. Treatment of cells with batimastat or GI254023X, inhibitors of the α-secretase ADAM10, prevented sAPPα generation and reduced cell survival. Additionally, inhibition of sAPPα significantly reduced anchorage independent growth of the cancer cells. The effect of batimastat on cell survival and colony formation was enhanced when sAPPα downregulation was combined with gemcitabine treatment. Moreover, treatment of batimastat-treated cells with recombinant sAPPα reversed the inhibitory effect of the drug thereby indicating that sAPPα can indeed induce proliferation of cancer cells. Down-regulation of APP and ADAM10 brought about similar results, as did batimastat treatment, thereby confirming that APP processing is important for growth and proliferation of these cells. These results suggest that inhibition of sAPPα generation might enhance the effectiveness of the existing chemotherapeutic regimen for a better outcome.

• Authors: Neha Kabra Woods, Jaya Padmanabhan
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 288 Issue 42 Pg. 30114-30124 (Oct 18 2013) ISSN: 1083-351X [Electronic] United States
• PMID: 24022491 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• 3-(formylhydroxyamino)-2-(3-phenyl-1-propyl)butanoic acid (2,2-dimethyl-1-methylcarbamoyl-1-propyl)amide
• APP protein, human
• Amyloid beta-Protein Precursor
• Antimetabolites, Antineoplastic
• Cytotoxins
• Dipeptides
• Hydroxamic Acids
• Membrane Proteins
• Neoplasm Proteins
• Protease Inhibitors
• Thiophenes
• Deoxycytidine
• Phenylalanine
• batimastat
• Amyloid Precursor Protein Secretases
• ADAM Proteins
• ADAM10 Protein
• ADAM10 protein, human
• Gemcitabine

Topics

• ADAM Proteins (antagonists & inhibitors, genetics, metabolism)
• ADAM10 Protein
• Amyloid Precursor Protein Secretases (antagonists & inhibitors, genetics, metabolism)
• Amyloid beta-Protein Precursor (genetics, metabolism)
• Antimetabolites, Antineoplastic (pharmacology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cytotoxins (genetics, metabolism)
• Deoxycytidine (analogs & derivatives, pharmacology)
• Dipeptides (pharmacology)
• Humans
• Hydroxamic Acids (pharmacology)
• Membrane Proteins (antagonists & inhibitors, genetics, metabolism)
• Neoplasm Proteins (antagonists & inhibitors, genetics, metabolism)
• Pancreatic Neoplasms (drug therapy, genetics, metabolism, pathology)
• Phenylalanine (analogs & derivatives, pharmacology)
• Protease Inhibitors (pharmacology)
• Protein Structure, Tertiary
• Thiophenes (pharmacology)
• Gemcitabine