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

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

Research output: Contribution to journalArticle

30 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)889-905
Number of pages17
JournalMolecular Oncology
Volume9
Issue number4
DOIs
StatePublished - Apr 1 2015

Keywords

  • Dasatinib
  • FTY-720
  • PP2A
  • Pancreatic cancer
  • Phenothiazine

ASJC Scopus subject areas

  • Molecular Medicine
  • Genetics
  • Oncology
  • Cancer Research

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  • Cite this

    Chien, W., Sun, Q. Y., Lee, K. L., Ding, L. W., Wuensche, P., Torres-Fernandez, L. A., Tan, S. Z., Tokatly, I., Zaiden, N., Poellinger, L., Mori, S., Yang, H., Tyner, J. W., & Koeffler, H. P. (2015). Activation of protein phosphatase 2A tumor suppressor as potential treatment of pancreatic cancer. Molecular Oncology, 9(4), 889-905. https://doi.org/10.1016/j.molonc.2015.01.002