title: 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: Cancer Science Institute of Singapore, National University of Singapore, Singapore. Electronic address: csicw@nus.edu.sg.
authors: Wenwen
authors: W
authors: Chien
authors: Cancer Science Institute of Singapore, National University of Singapore, Singapore.
authors: Qiao-Yang
authors: QY
authors: Sun
authors: Cancer Science Institute of Singapore, National University of Singapore, Singapore.
authors: Kian Leong
authors: KL
authors: Lee
authors: Cancer Science Institute of Singapore, National University of Singapore, Singapore.
authors: Ling-Wen
authors: LW
authors: Ding
authors: Cancer Science Institute of Singapore, National University of Singapore, Singapore.
authors: Peer
authors: P
authors: Wuensche
authors: Cancer Science Institute of Singapore, National University of Singapore, Singapore.
authors: Lucia A
authors: LA
authors: Torres-Fernandez
authors: Cancer Science Institute of Singapore, National University of Singapore, Singapore.
authors: Siew Zhuan
authors: SZ
authors: Tan
authors: Cancer Research Center, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel Hashomer 52621, Israel.
authors: Itay
authors: I
authors: Tokatly
authors: Cancer Science Institute of Singapore, National University of Singapore, Singapore.
authors: Norazean
authors: N
authors: Zaiden
authors: Cancer Science Institute of Singapore, National University of Singapore, Singapore.
authors: Lorenz
authors: L
authors: Poellinger
authors: Cancer Science Institute of Singapore, National University of Singapore, Singapore.
authors: Seiichi
authors: S
authors: Mori
authors: Cancer Science Institute of Singapore, National University of Singapore, Singapore.
authors: Henry
authors: H
authors: Yang
authors: Department of Cell & Developmental Biology, Oregon Health & Science University, Portland, OR 97239, USA.
authors: Jeffrey W
authors: JW
authors: Tyner
authors: Cancer Science Institute of Singapore, National University of Singapore, Singapore; Cedars-Sinai Medical Center, UCLA School of Medicine, Los Angeles, CA, USA; National University Cancer Institute, Singapore.
authors: H Phillip
authors: HP
authors: Koeffler
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003198:Computer Simulation; D000069439:Dasatinib / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical; D004789:Enzyme Activation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics; D010395:Penfluridol / Q000494:pharmacology / Q000627:therapeutic use; D010640:Phenothiazines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D054648:Protein Phosphatase 2 / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D010640:Phenothiazines; D047428:Protein Kinase Inhibitors; D025521:Tumor Suppressor Proteins; D010395:Penfluridol; D054648:Protein Phosphatase 2; C031637:phenothiazine; D000069439:Dasatinib
keywords: Dasatinib; FTY-720; PP2A; Pancreatic cancer; Phenothiazine
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