Activation of protein phosphatase 2A tumor suppressor as potential treatment of pancreatic cancer.

Abstract

We utilized three tiers of screening to identify novel therapeutic agents for pancreatic cancers. First, we analyzed 14 pancreatic cancer cell lines against a panel of 66 small-molecule kinase inhibitors and dasatinib was the most potent. Second, we performed RNA expression analysis on 3 dasatinib-resistant and 3 dasatinib-sensitive pancreatic cancer cell lines to profile their gene expression. Third, gene profiling data was integrated with the Connectivity Map database to search for potential drugs. Thioridazine was one of the top ranking small molecules with highly negative enrichment. Thioridazine and its family members of phenothiazine including penfluridol caused pancreatic cancer cell death and affected protein expression levels of molecules involved in cell cycle regulation, apoptosis, and multiple kinase activities. This family of drugs causes activation of protein phosphatase 2 (PP2A). The drug FTY-720 (activator of PP2A) induced apoptosis of pancreatic cancer cells. Silencing catalytic unit of PP2A rendered pancreatic cancer cells resistant to penfluridol. Our observations suggest potential therapeutic use of penfluridol or similar agent associated with activation of PP2A in pancreatic cancers.

• Authors: Wenwen Chien, Qiao-Yang Sun, Kian Leong Lee, Ling-Wen Ding, Peer Wuensche, Lucia A Torres-Fernandez, Siew Zhuan Tan, Itay Tokatly, Norazean Zaiden, Lorenz Poellinger, Seiichi Mori, Henry Yang, Jeffrey W Tyner, H Phillip Koeffler
• Journal: Molecular oncology (Mol Oncol) Vol. 9 Issue 4 Pg. 889-905 (Apr 2015) ISSN: 1878-0261 [Electronic] United States
• PMID: 25637283 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

Chemical References

• Antineoplastic Agents
• Phenothiazines
• Protein Kinase Inhibitors
• Tumor Suppressor Proteins
• Penfluridol
• Protein Phosphatase 2
• phenothiazine
• Dasatinib

Topics

• Antineoplastic Agents (pharmacology, therapeutic use)
• Apoptosis (drug effects)
• Cell Cycle (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Computer Simulation
• Dasatinib (pharmacology)
• Drug Evaluation, Preclinical
• Enzyme Activation (drug effects)
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Inhibitory Concentration 50
• Pancreatic Neoplasms (drug therapy, enzymology, genetics)
• Penfluridol (pharmacology, therapeutic use)
• Phenothiazines (pharmacology)
• Protein Kinase Inhibitors (pharmacology)
• Protein Phosphatase 2 (metabolism)
• Tumor Suppressor Proteins (metabolism)