title: Growth of the pancreatic cancer cell line PANC-1 is inhibited by protein phosphatase 2A inhibitors through overactivation of the c-Jun N-terminal kinase pathway.
abstract: Protein phosphatase 2A (PP2A) is a multimeric serine/threonine phosphatase that can dephosphorylate multiple kinases. It is generally considered to be a cancer suppressor as its inhibition can induce phosphorylation and activation of substrate kinases that mainly accelerate growth. We previously reported that cantharidin, an active constituent of a traditional Chinese medicine, potently and selectively inhibited PP2A, yet efficiently repressed the growth of pancreatic cancer cells through activation of the c-Jun N-terminal kinase (JNK) pathway. This suggested that activation of kinase pathways might also be a potential strategy for cancer therapy. In this study, we have confirmed that the basal activity of the phospatidylinositol 3-kinase (PI3K)/JNK/activator protein 1 (AP-1) pathway promoted pancreatic cancer cell growth when stimulated by growth factors. Interestingly, although treatment with the PP2A inhibitors, cantharidin or okadaic acid (OA), amplified the PI3K-dependent activation of JNK, cell growth was repressed. We therefore hypothesised that a specific level of activity of the JNK pathway might be required to maintain the promitogenic function, as both repression and overactivation of JNK could inhibit cell proliferation. It was found that the JNK-dependent growth inhibition was independent of the activation of AP-1, but dependent on the repression of Akt. Although the PP2A inhibitors triggered overactivation of JNK and inhibited cell growth, excessively activated protein kinase C (PKC) improved cell survival. Combined treatment with a PP2A inhibitor and a PKC inhibitor produced a synergistic effect, which indicates a potentially promising therapeutic approach to pancreatic cancer treatment.
authors.affiliation: Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.forename: Zheng
authors.initials: Z
authors.lastname: Chen
authors.forename: Fei-Ran
authors.initials: FR
authors.lastname: Gong
authors.forename: Yang
authors.initials: Y
authors.lastname: Zong
authors.forename: Kai
authors.initials: K
authors.lastname: Chen
authors.forename: Dao-Ming
authors.initials: DM
authors.lastname: Li
authors.forename: Hong
authors.initials: H
authors.lastname: Yin
authors.forename: Wei-Ming
authors.initials: WM
authors.lastname: Duan
authors.forename: Yi
authors.initials: Y
authors.lastname: Miao
authors.forename: Min
authors.initials: M
authors.lastname: Tao
authors.forename: Xiao
authors.initials: X
authors.lastname: Han
authors.forename: Ze-Kuan
authors.initials: ZK
authors.lastname: Xu
mesh_terms: D002193:Cantharidin / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000494:pharmacology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008156:Luciferases / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000494:pharmacology; D009687:Nuclear Proteins; D019319:Okadaic Acid / Q000494:pharmacology; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000201:enzymology*; D016133:Polymerase Chain Reaction; D054648:Protein Phosphatase 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D016601:RNA-Binding Proteins
chemical_list: C087425:ANP32A protein, human; D004791:Enzyme Inhibitors; C063306:HINT1 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D016601:RNA-Binding Proteins; D019319:Okadaic Acid; D008156:Luciferases; D051057:Proto-Oncogene Proteins c-akt; D048031:JNK Mitogen-Activated Protein Kinases; D054648:Protein Phosphatase 2; D002193:Cantharidin