title: FTY720 inhibits mesothelioma growth in vitro and in a syngeneic mouse model.
abstract: Malignant mesothelioma (MM) is a very aggressive type of cancer, with a dismal prognosis and inherent resistance to chemotherapeutics. Development and evaluation of new therapeutic approaches is highly needed. Immunosuppressant FTY720, approved for multiple sclerosis treatment, has recently raised attention for its anti-tumor activity in a variety of cancers. However, its therapeutic potential in MM has not been evaluated yet.
  
  
  
  Cell viability and anchorage-independent growth were evaluated in a panel of MM cell lines and human mesothelial cells (HM) upon FTY720 treatment to assess in vitro anti-tumor efficacy. The mechanism of action of FTY720 in MM was assessed by measuring the activity of phosphatase protein 2A (PP2A)-a major target of FTY720. The binding of the endogenous inhibitor SET to PP2A in presence of FTY720 was evaluated by immunoblotting and immunoprecipitation. Signaling and activation of programmed cell death were evaluated by immunoblotting and flow cytometry. A syngeneic mouse model was used to evaluate anti-tumor efficacy and toxicity profile of FTY720 in vivo.
  
  
  
  We show that FTY720 significantly suppressed MM cell viability and anchorage-independent growth without affecting normal HM cells. FTY720 inhibited the phosphatase activity of PP2A by displacement of SET protein, which appeared overexpressed in MM, as compared to HM cells. FTY720 promoted AKT dephosphorylation and Bcl-2 degradation, leading to induction of programmed cell death, as demonstrated by caspase-3 and PARP activation, as well as by cytochrome c and AIF intracellular translocation. Moreover, FTY720 administration in vivo effectively reduced tumor burden in mice without apparent toxicity.
  
  
  
  Our preclinical data indicate that FTY720 is a potentially promising therapeutic agent for MM treatment.
authors.affiliation: Thoracic Oncology Program, University of Hawaii Cancer Center, 701 Ilalo Street, Honolulu, HI, 96813, USA.
authors.forename: Agata
authors.initials: A
authors.lastname: Szymiczek
authors.affiliation: Thoracic Oncology Program, University of Hawaii Cancer Center, 701 Ilalo Street, Honolulu, HI, 96813, USA. pastorin@hawaii.edu.
authors.forename: Sandra
authors.identifier: 0000-0002-4559-1065
authors.initials: S
authors.lastname: Pastorino
authors.affiliation: Thoracic Oncology Program, University of Hawaii Cancer Center, 701 Ilalo Street, Honolulu, HI, 96813, USA.
authors.forename: David
authors.initials: D
authors.lastname: Larson
authors.affiliation: Thoracic Oncology Program, University of Hawaii Cancer Center, 701 Ilalo Street, Honolulu, HI, 96813, USA.
authors.forename: Mika
authors.initials: M
authors.lastname: Tanji
authors.affiliation: Thoracic Oncology Program, University of Hawaii Cancer Center, 701 Ilalo Street, Honolulu, HI, 96813, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Pellegrini
authors.affiliation: Thoracic Oncology Program, University of Hawaii Cancer Center, 701 Ilalo Street, Honolulu, HI, 96813, USA.
authors.forename: Jiaming
authors.initials: J
authors.lastname: Xue
authors.affiliation: Thoracic Oncology Program, University of Hawaii Cancer Center, 701 Ilalo Street, Honolulu, HI, 96813, USA.
authors.forename: Shuangjing
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Morphology-Surgery-Experimental Medicine, University of Ferrara, Ferrara, Italy.
authors.forename: Carlotta
authors.initials: C
authors.lastname: Giorgi
authors.affiliation: Department of Morphology-Surgery-Experimental Medicine, University of Ferrara, Ferrara, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Pinton
authors.affiliation: Thoracic Oncology Program, University of Hawaii Cancer Center, 701 Ilalo Street, Honolulu, HI, 96813, USA.
authors.forename: Yasutaka
authors.initials: Y
authors.lastname: Takinishi
authors.affiliation: Department of Cardiothoracic Surgery, New York University Langone Medical Center, New York, NY, 10065, USA.
authors.forename: Harvey I
authors.initials: HI
authors.lastname: Pass
authors.affiliation: Thoracic Oncology Program, University of Hawaii Cancer Center, 701 Ilalo Street, Honolulu, HI, 96813, USA.
authors.forename: Hideki
authors.initials: H
authors.lastname: Furuya
authors.affiliation: Thoracic Oncology Program, University of Hawaii Cancer Center, 701 Ilalo Street, Honolulu, HI, 96813, USA.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Gaudino
authors.affiliation: Thoracic Oncology Program, University of Hawaii Cancer Center, 701 Ilalo Street, Honolulu, HI, 96813, USA.
authors.forename: Andrea
authors.initials: A
authors.lastname: Napolitano
authors.affiliation: Thoracic Oncology Program, University of Hawaii Cancer Center, 701 Ilalo Street, Honolulu, HI, 96813, USA. mcarbone@cc.hawaii.edu.
authors.forename: Michele
authors.initials: M
authors.lastname: Carbone
authors.affiliation: Thoracic Oncology Program, University of Hawaii Cancer Center, 701 Ilalo Street, Honolulu, HI, 96813, USA. hyang@cc.hawaii.edu.
authors.forename: Haining
authors.initials: H
authors.lastname: Yang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D000068876:Fingolimod Hydrochloride / Q000494:pharmacology / Q000627:therapeutic use* / Q000633:toxicity; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D008654:Mesothelioma / Q000188:drug therapy* / Q000473:pathology*; D000086002:Mesothelioma, Malignant; D051379:Mice; D054648:Protein Phosphatase 2 / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism
chemical_list: D025521:Tumor Suppressor Proteins; D054648:Protein Phosphatase 2; D000068876:Fingolimod Hydrochloride
keywords: Apoptosis; Drug repurposing; FTY720; Malignant mesothelioma; PP2A; Therapeutic